Basic Biology and Clinical Aspects of Inflammation [1 ed.] 9781681082271, 9781681082288

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Frontiers in Inflammation (Volume 1) Basic Biology and Clinical Aspects of Inflammation Edited By Robert F. Diegelmann & Charles E. Chalfant Department of Biochemistry and Molecular Biology Virginia Commonwealth University Medical Center 1101 East Marshall Street Sanger Hall, Room 2-007 Richmond Virginia, 23298-0614 USA

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CONTENTS FOREWORD ................................................................................................................................................................ i PREFACE ................................................................................................................................................................... iii LIST OF CONTRIBUTORS ..................................................................................................................................... iv CHAPTER 1 INTRODUCTION TO BASIC BIOLOGY AND CLINICAL ASPECTS OF INFLAMMATION ......................................................................................................................................................................................... 3 INTRODUCTION ................................................................................................................................................ 3 CHAPTER 2 ......................................................................................................................................................... 5 CHAPTER 3 ......................................................................................................................................................... 5 CHAPTER 4 ......................................................................................................................................................... 5 CHAPTER 5 ......................................................................................................................................................... 5 CHAPTER 6 ......................................................................................................................................................... 6 CHAPTER 7 ........................................................................................................................................................ 6 CHAPTER 8 ......................................................................................................................................................... 6 CHAPTER 9 ......................................................................................................................................................... 6 CHAPTER 10 ....................................................................................................................................................... 6 CHAPTER 11 ....................................................................................................................................................... 7 CHAPTER 12 ....................................................................................................................................................... 7 CHAPTER 13 ....................................................................................................................................................... 7 CHAPTER 14 ....................................................................................................................................................... 8 CHAPTER 15 ....................................................................................................................................................... 8 CHAPTER 16 ....................................................................................................................................................... 8 CONFLICT OF INTEREST ............................................................................................................................... 9 ACKNOWLEDGEMENTS ................................................................................................................................. 9 REFERENCES ..................................................................................................................................................... 9 CHAPTER 2 CELL MEDIATORS OF ACUTE INFLAMMATION ............................................................... INTRODUCTION .............................................................................................................................................. Toll-like Receptors ....................................................................................................................................... Mast Cells ..................................................................................................................................................... Triggers of Mast Cell Degranulation ........................................................................................................... Mediators Released by Mast Cells ............................................................................................................... NEUTROPHILS ................................................................................................................................................. MACROPHAGES ............................................................................................................................................. Macrophage Function and Phenotypes ........................................................................................................ ADAPTIVE IMMUNE CELLS IN ACUTE INFLAMMATION .................................................................. Gamma Delta T Cells ................................................................................................................................... TH17 T Lymphocytes .................................................................................................................................. SUMMARY ......................................................................................................................................................... CONFLICT OF INTEREST ............................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................... REFERENCES ...................................................................................................................................................

11 11 13 13 14 15 16 17 18 21 21 22 22 23 23 23

CHAPTER 3 BIOCHEMICAL MEDIATORS OF INFLAMMATION AND RESOLUTION ...................... 26 INTRODUCTION .............................................................................................................................................. 27 BIOSYNTHESIS OF LIPID MEDIATORS .................................................................................................... 28

7KHGHVLJQHGFRYHULPDJHLVFUHDWHGE\%HQWKDP6FLHQFHDQG%HQWKDP6FLHQFHKROGVWKHFRS\ULJKWVIRUWKHLPDJH

Phospholipase A2 ........................................................................................................................................ Group IVA Cytosolic Phospholipase A2 (cPLA2α) .................................................................................... Secretory Phospholipase A2 (sPLA2) .......................................................................................................... Group VIA Phospholipase A2 (iPLA2β) ..................................................................................................... Eicosanoid Production Pathways ................................................................................................................. Cyclooxygenase (COX) Pathway ................................................................................................................. Lipoxygenase Pathway ................................................................................................................................. Cytochrome P450 Pathway .......................................................................................................................... PRO-INFLAMMATORY LIPID MEDIATORS ............................................................................................ PRO-RESOLUTION LIPID MEDIATORS .................................................................................................... BIOSYNTHEIS OF CYTOKINES AND CHEMOKINES ............................................................................ PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES .................................................................. PRO-RESOLUTION CYTOKINES AND CHEMOKINES .......................................................................... CONCLUSION ................................................................................................................................................... CONFLICT OF INTEREST ............................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................... REFERENCES ...................................................................................................................................................

28 29 31 31 32 33 33 34 35 37 39 40 41 42 42 42 43

CHAPTER 4 WOUND HEALING AND DERMATOLOGIC ASPECTS OF INFLAMMATION ............... INTRODUCTION .............................................................................................................................................. NORMAL DERMATOLOGICAL RESPONSE IN WOUND HEALING ................................................... The Inflammatory Phase of Wound Healing ................................................................................................ Neutrophils ................................................................................................................................................... Monocytes and Macrophages ....................................................................................................................... T lymphocytes .............................................................................................................................................. The Proliferative Phase ................................................................................................................................ The Remodeling or Maturation Phase ......................................................................................................... WHY DON’T CHRONIC WOUNDS HEAL? ................................................................................................ COMMON WOUND HEALING PROBLEMS AND INFLAMMATION .................................................. Diabetes ........................................................................................................................................................ Venous Insufficiency .................................................................................................................................... Aging and Wound Repair ............................................................................................................................. Pyoderma Gangrenosum .............................................................................................................................. CONCLUSION ................................................................................................................................................... CONFLICT OF INTEREST ............................................................................................................................. ACKNOWLEDGEMENTS ............................................................................................................................... REFERENCES ...................................................................................................................................................

55 55 56 57 57 58 60 61 61 62 64 64 65 67 69 73 74 74 74

CHAPTER 5 METABOLIC REGULATION OF INFLAMMATION ............................................................. INTRODUCTION .............................................................................................................................................. INFLAMMATION AS A LINK BETWEEN OBESITY AND METABOLIC SYNDROME .................... CLASSIC INFLAMMATION VS. METABOLIC INFLAMMATION ....................................................... MOLECULAR PATHWAYS THAT LINK INFLAMMATION AND INSULIN RESISTANCE ............ RESIDENT AND INFILTRATED IMMUNE CELLS IN ADIPOSE TISSUE ........................................... Macrophages ................................................................................................................................................ Lymphocytes ................................................................................................................................................ Mast Cells and Eosinophils .......................................................................................................................... THERAPEUTIC OPPORTUNITIES FOR METABOLIC DISEASES ....................................................... Anti-Inflammation Therapeutics .................................................................................................................. Reverse the Imbalance of Excess Caloric Intake and Energy Expenditure: A Second Thought ................. CONCLUSION ...................................................................................................................................................

83 83 84 85 86 89 90 91 94 94 94 95 96

CONFLICT OF INTEREST ............................................................................................................................. 97 ACKNOWLEDGEMENTS ............................................................................................................................... 97 REFERENCES ................................................................................................................................................... 97 CHAPTER 6 AGING AND INFLAMMATION ................................................................................................ 106 INTRODUCTION ............................................................................................................................................ 106 Immunosenescence .................................................................................................................................... 107 Inflammaging ............................................................................................................................................. 107 BIOLOGICAL AND MOLECULAR BASIS FOR AGING-ASSOCIATED CHRONIC INFLAMMATION ..................................................................................................................................................................... 109 Introduction ................................................................................................................................................ 109 Changes in the Basal Levels of Systemic Inflammatory Mediators in Human and Rodents during Aging ............................................................................................................................................................. 110 Molecular and Cellular Mechanisms for Aging-Associated Induction of Cytokine Production in the Absence of Infection ........................................................................................................................................ 113 Aging-Associated Changes in the Homeostasis of Bioactive Lipid Metabolites ....................................... 117 THE CONCEPT OF CELLULAR HYPERRESPONSIVENESS TO PRO-INFLAMMATORY AGONISTS ............................................................................................................................................. 119 DIETARY AND PHARMACOLOGICAL INTERVENTIONS THAT SUPPRESS AGING-ASSOCIATED RISE IN INFLAMMATORY MARKERS ............................................................................................ 122 Caloric Restriction ...................................................................................................................................... 123 Other Dietary Approaches that Attenuate Inflammaging ........................................................................... 124 Exercise ...................................................................................................................................................... 125 CONCLUDING REMARKS ........................................................................................................................... 125 CONFLICT OF INTEREST ........................................................................................................................... 126 ACKNOWLEDGEMENTS ............................................................................................................................. 127 REFERENCES ................................................................................................................................................. 127 CHAPTER 7 ALLERGIC INFLAMMATION .................................................................................................. INTRODUCTION ............................................................................................................................................ CELLS INVOLVED IN ALLERGIC INFLAMMATION .......................................................................... T Lymphocytes ........................................................................................................................................... B Lymphocytes .......................................................................................................................................... Eosinophils ................................................................................................................................................. Basophils .................................................................................................................................................... Mast Cells ................................................................................................................................................... Innate Lymphoid Type 2 Cells .................................................................................................................. Conclusion .................................................................................................................................................. INNATE CYTOKINES INVOLVED IN TH2 IMMUNE BIAS .................................................................. Interleukin-25 ............................................................................................................................................. Interleukin-33 ............................................................................................................................................. Thymic Stromal Lymphopoietin ................................................................................................................ Pharmacologic Modulation of Innate Cytokines Important in TH2 Immunity .......................................... ADAPTIVE CYTOKINES INVOLVED IN TH2 IMMUNE BIAS ........................................................... Interleukin-4 ............................................................................................................................................... Interleukin-13 ............................................................................................................................................. Interleukin-5 ............................................................................................................................................... Interleukin-9 ............................................................................................................................................... Interleukin-3 ............................................................................................................................................... Granulocyte-Monocyte Colony Stimulating Factor ................................................................................... Interleukin-10 .............................................................................................................................................

138 138 139 143 145 145 146 146 147 147 148 148 149 149 150 150 151 152 152 152 153 153 153

Pharmacologic Modulation of Adaptive Cytokines Important in TH2 Immunity ..................................... CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

154 155 156 156 156

CHAPTER 8 INFLAMMATION IN TYPE 2 DIABETES ............................................................................... INTRODUCTION ............................................................................................................................................ INFLAMMATORY MECHANISMS IN THE PATHOGENESIS OF DIABETES ................................ Inflammatory Mechanisms of Beta Cell Dysfunction/Failure in Diabetes ................................................ Inflammation in Adipose Tissue and Insulin Resistance ........................................................................... Tissue Hypoxia ................................................................................................................................... Adipocyte Cell Death ......................................................................................................................... NF-KB and JNK Pathways ................................................................................................................. M2 Vs M1 Macrophages Phenotype .................................................................................................. INFLAMMATION IN THE DEVELOPMENT OF DIABETES COMPLICATIONS ........................... AGE/RAGE Signalling and Inflammation in Diabetes .............................................................................. Oxidative Stress and Inflammation ............................................................................................................ INFLAMMATION IN SPECIFIC DIABETES COMPLICATIONS ......................................................... Diabetic Nephropathy ................................................................................................................................ Diabetic Neuropathy .................................................................................................................................. Diabetic Foot/Charcot ................................................................................................................................ CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

164 164 165 165 167 167 167 168 168 169 169 170 171 171 172 173 174 174 175 175

CHAPTER 9 THE VASCULAR TREE AND HEART WITH RELATIONSHIP TO INFLAMMATION 180 INTRODUCTION ............................................................................................................................................ Endothelial Cell Biology (The Link Between Blood and Tissue) ............................................................. Coagulation/Inflammation Interface .......................................................................................................... Microvascular Architecture ........................................................................................................................ Hemoglobin/Inflammation ......................................................................................................................... Platelet EC Interactions .............................................................................................................................. Chemokines ................................................................................................................................................ Atherosclerosis- Chronic Vascular Inflammation ...................................................................................... Vasculitis .................................................................................................................................................... CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

... 180 186 190 192 193 193 199 199 207 208 208 209 209

CHAPTER 10 RHEUMATOID AND DEGENERATIVE ARTHRITIS-ASSOCIATED INFLAMMATION ..................................................................................................................................................................................... 220 INTRODUCTION ............................................................................................................................................ 221 ANATOMICAL AND PHYSIOLOGICAL BACKGROUND .................................................................... 222 Defining the Joint ....................................................................................................................................... 222 Joint Capsule, Synovium and Synovial Fluid ............................................................................................ 223 Articular Cartilage ...................................................................................................................................... 223 TERMINOLOGICAL NOTES ON INFLAMMATION AND ARTHRITIS REFLECTING ELUSIVE

PATHOGENESIS .................................................................................................................................... 225 CLINICAL PRESENTATIONS ..................................................................................................................... 226 EPIDEMIOLOGY ........................................................................................................................................... 229 ETIOPATHOGENESIS OF RHEUMATOID AND DEGENERATIVE ARTHRITIS ........................... 230 Overall Pathophysiology ............................................................................................................................ 230 Contribution of the Genetic Background ................................................................................................... 232 Influence of Epigenetic Modifications ....................................................................................................... 234 Features Predominant to Rheumatoid Arthritis Pathology; Adaptive Immunological Events .................. 235 B-lymphocytes and Autoantibody Production .................................................................................... 235 T-cell Activation ................................................................................................................................. 235 Activation of Synovial Fibroblasts ............................................................................................................. 236 Effects Deriving from Innate Immunity .................................................................................................... 237 Intracellular Signaling via Toll-like Receptors ......................................................................................... 237 Complement Activation ............................................................................................................................. 239 Important Common Pro-inflammatory Mediators of Arthritic Inflammation ........................................... 239 DIAGNOSTIC PATHS IN CLINICAL DISEASE MANAGEMENT ....................................................... 241 CURRENT THERAPEUTIC PROCEDURES, ACTUAL LIMITATIONS AND POTENTIAL FUTURE OPTIONS .................................................................................................................................................. 242 CONCLUDING REMARKS AND FUTURE PERSPECTIVES ................................................................ 244 CONFLICT OF INTEREST ........................................................................................................................... 245 ACKNOWLEDGEMENTS ............................................................................................................................. 245 REFERENCES ................................................................................................................................................. 245 CHAPTER 11 INFLAMMATION IN ORAL DISEASES ................................................................................ INTRODUCTION ............................................................................................................................................ a. The Unique Niche of the Oral Cavity .................................................................................................... b. Microbial Environment ......................................................................................................................... c. Oral Mucosal Inflammation and Immune Responses ........................................................................... d. Sublingual Immunotherapy ................................................................................................................... e. Mediators of Oral Inflammation ............................................................................................................ INFLAMMATION IN ORAL HEALTH AND DISEASES ........................................................................ a. Wound Healing ...................................................................................................................................... b. Autoimmune Mucosal Diseases ............................................................................................................ c. Dental Caries .......................................................................................................................................... d. Periodontal Diseases .............................................................................................................................. e. Reactive Oral Lesions ............................................................................................................................. f. Infectious Diseases .................................................................................................................................. g. Malignancies .......................................................................................................................................... ANTI-INFLAMMATORY STRATEGIES IN ORAL DISEASES ............................................................ a. Mechanical ............................................................................................................................................. b. Biochemical ............................................................................................................................................ c. Innovative New Therapies ...................................................................................................................... CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

254 254 254 255 256 259 260 261 261 262 264 265 267 270 271 274 274 275 277 279 280 280 280

CHAPTER 12 INTESTINAL INFLAMMATION AND INFLAMMATORY BOWEL DISEASE ............. INTRODUCTION ............................................................................................................................................ LESSONS LEARNED FROM LINKAGE ANALYSIS AND GWAS ........................................................ ALTERATIONS IN THE GUT MICROBIOME IN IBD ............................................................................

292 292 293 295

DYSBIOSIS CONTRIBUTES TO INTESTINAL INFLAMMATION ...................................................... ALTERED IMMUNE RESPONSES TO MICROBIAL PRODUCTS ....................................................... ALTERED INTESTINAL BARRIER FUNCTION AND PERMEABILITY ........................................... ALTERATIONS IN THE ADAPTIVE IMMUNE RESPONSE ................................................................. CONCLUSION ................................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

296 297 298 299 299 300 300 300

CHAPTER 13 NEUROINFLAMMATION ........................................................................................................ INTRODUCTION ............................................................................................................................................ CENTRAL NERVOUS SYSTEM INNATE IMMUNE RESPONSE ......................................................... Microglia .................................................................................................................................................... Surveying (Resting) Microglia .......................................................................................................... Activated Microglia ............................................................................................................................ Astrocyte .................................................................................................................................................... Activating Signals ...................................................................................................................................... Toll-Like Receptors (TLR) .................................................................................................................. Retinoic Acid-Inducible Gene 1 (RIG-I) and RIG-I-Like Receptors .................................................. Inflammasome Sensors: NOD-Like Receptors .................................................................................. Purinergic Receptors .......................................................................................................................... Inhibitory Signals ....................................................................................................................................... CX3CL1/CX3CR1 ............................................................................................................................... CD200/CD200R ................................................................................................................................. Effector Mechanisms .................................................................................................................................. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase Complex .................................. Nitric Oxide Synthase 2 ...................................................................................................................... Inflammasome/interleukin-1β ............................................................................................................. Interleukin-6 ....................................................................................................................................... TNF ..................................................................................................................................................... CENTRAL NERVOUS SYSTEM ADAPTIVE IMMUNE RESPONSE/AUTOIMMUNITY ................. CNS Immune Privilege .............................................................................................................................. CNS Trafficking/Cell Recruitment ............................................................................................................ Integrins ............................................................................................................................................. Chemokines ........................................................................................................................................ Cell-Mediated CNS Inflammation ............................................................................................................. Encephalitogenic CD4+ T Lymphocyte: Th1 Versus Th17 ............................................................... Humoral Mediated CNS Inflammation ...................................................................................................... Auto-Reactive Antibodies against CNS Antigens ............................................................................... PERSPECTIVES .............................................................................................................................................. CONFLICT OF INTEREST ........................................................................................................................... ACKNOWLEDGEMENTS ............................................................................................................................. REFERENCES .................................................................................................................................................

305 305 307 307 309 310 310 312 313 316 317 318 319 320 321 323 323 325 328 329 331 333 334 337 338 339 339 340 342 343 344 345 345 345

CHAPTER 14 PHARMACOTHERAPY FOR INFLAMMATORY PROCESSES ....................................... 377 INTRODUCTION AND SCOPE OF THE CHAPTER ............................................................................... 377 The Spectrum of Currently Used Anti-Inflammatory Drugs: Their Utility in Identifying the ‘Power Brokers’ of Inflammatory Disease .................................................................................................................... 380 Drugs Targeting the Release and Effects of Histamine ............................................................................. 383 The Eicosanoids: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and other Approaches to Control their Activity ............................................................................................................................................... 385

Prostanoids and their Regulation ................................................................................................................ 387 Therapeutic Exploitation of Prostanoids and their Receptors .................................................................... 391 Leukotrienes and their Regulation ............................................................................................................. 392 Platelet-Activating Factor (PAF): A potent Lipid-Derived Mediator that has so far Failed to Deliver as a Drug Target ........................................................................................................................................ 394 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) .................................................................................. 395 Conventional NSAIDs ................................................................................................................................ 396 COX-2 Selective NSAIDs (Coxibs) ........................................................................................................... 399 Glucocorticosteroids ................................................................................................................................... 400 Dose and Indication Limiting Adverse Effects of Glucocorticoids ........................................................... 402 Disease-Modifying Anti-Rheumatic Drugs (DMARDS)- An Effective ‘Hodgepodge’ of Compounds. ............................................................................................................................................................. 404 Immunosuppressant Anti-Inflammatory Drugs ......................................................................................... 406 Cytotoxic Agents ........................................................................................................................................ 407 Biological Anti-Inflammatory Drugs ......................................................................................................... 408 Being Thankful for What We’ve Got! ....................................................................................................... 411 The Evolving Spectrum of Anti-Inflammatory Drugs- New Drugs on the Horizon .................................. 411 Drugs Targeting Cell Signalling Mechanisms ........................................................................................... 411 Janus Kinase (JAK), Signal Transducer of Activators of Transcription (STAT) (JAK-STAT) Pathway Inhibitors .................................................................................................................................... 412 Spleen Tyrosine Kinase (Syk) Inhibitors ............................................................................................ 412 SH2-Containing Inositol 5’-Phosphatase (SHIP) Activators ............................................................. 413 Interleukin-1 Receptor-Associated Kinase (IRAK) Inhibitors ........................................................... 414 NLRP3 Inflammasome Inhibitors ....................................................................................................... 414 Extracellular Enzyme Targets .................................................................................................................... 415 Thrombin and Factors Xa/XIIIa ......................................................................................................... 415 Neutrophil Elastase and Matrix Metalloproteinases (MMPs) ........................................................... 416 Emerging Antibody Therapies- New Antibodies, New Indications, New Precision Use ................... 417 Antibody Engineering and Antibody Alternatives .............................................................................. 418 Nucleic Acid-Based Therapies .......................................................................................................... 418 SUMMARY AND CONCLUSION ................................................................................................................. 420 CONFLICT OF INTEREST ........................................................................................................................... 420 ACKNOWLEDGEMENTS ............................................................................................................................. 421 REFERENCES ................................................................................................................................................. 421 CHAPTER 15 MATHEMATICAL MODELING OF INFLAMMATION ..................................................... INTRODUCTION ............................................................................................................................................ MODELING OVERVIEW .............................................................................................................................. DETERMINISTIC MODELS ......................................................................................................................... Continuous Time ........................................................................................................................................ Continuous Time, Continuous Space ......................................................................................................... STOCHASTIC MODELS ............................................................................................................................... Discrete Time, Discrete Space ................................................................................................................... SPECIFIC MODELS OF INFLAMMATION ............................................................................................. SKIN AND WOUND HEALING .................................................................................................................... LUNG ................................................................................................................................................................ GASTROINTESTINAL .................................................................................................................................. DENTAL ........................................................................................................................................................... CANCER ........................................................................................................................................................... RHEUMATOID ARTHRITIS ....................................................................................................................... CONCLUDING REMARKS ...........................................................................................................................

427 427 428 429 429 432 434 434 436 436 437 438 441 442 443 445

CONFLICT OF INTEREST ........................................................................................................................... 446 ACKNOWLEDGEMENTS ............................................................................................................................. 446 REFERENCES ................................................................................................................................................. 446 CHAPTER 16 NETWORK ANALYSIS OF INFLAMMATION .................................................................... 451 INTRODUCTION ............................................................................................................................................ 451 Increased Interpretability of Experimental Results from Profiling Experiments ....................................... 452 Discovery of New Relationships between Endpoints in Profiling Experiments ........................................ 453 Increased Robustness of Discoveries with respect to Experimental Noise ................................................ 453 BIOLOGICAL NETWORKS: TYPES OF INTERACTIONS AND MAJOR REPOSITORIES AND DATABASES .......................................................................................................................................... 453 Protein-Protein Interaction Networks ......................................................................................................... 454 Gene Regulatory Networks ........................................................................................................................ 456 Metabolic Networks ................................................................................................................................... 456 NETWORK ANALYSIS TECHNIQUES FOR INFERRING GENE CONNECTIVITY FROM DATA ..................................................................................................................................................................... 457 Clustering Methods .................................................................................................................................... 457 Correlation-Based and Information-Theoretic Methods ............................................................................ 457 Machine-Learning Methods ....................................................................................................................... 458 NETWORK ANALYSIS TECHNIQUES FOR DISCOVERING NETWORKS THAT DIFFERENTIATE PHENOTYPES ......................................................................................................................................... 458 Network Methods Based on Univariate Tests of Differences .................................................................... 459 Gene Set-Based Methods .................................................................................................................... 460 Graph-Based Methods ........................................................................................................................ 461 Multivariate Network-Based Methods ....................................................................................................... 463 NETWORK ANALYSIS IN STUDIES OF INFLAMMATION ................................................................. 465 CONCLUDING REMARKS ........................................................................................................................... 467 CONFLICT OF INTEREST ........................................................................................................................... 468 ACKNOWLEDGEMENTS ............................................................................................................................. 468 REFERENCES ................................................................................................................................................. 468 SUBJECT INDEX .................................................................................................................................................... 474

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FOREWORD In the post-genomic era, understanding inflammation and its intricate mechanisms is the final frontier. While ancient physicians recognized inflammation’s cardinal signs as heat, redness, swelling and pain centuries ago,the cellular and molecular players in this vital inflammatory host response have only been elucidated for the most part in the last century. Today, it’s now well appreciated that uncontrolled inflammation and excessive tissue levels of inflammatory mediators play central roles in the pathogenesis of many widely occurring diseases throughout the body and all its organs. At one time, the study of inflammation and inflammatory diseases was confined to chronic inflammatory diseases such as rheumatoid arthritis, periodontal disease and the like, while today it is commonly appreciated that neurodegenerative diseases, cognitive decline, vascular diseases, asthma, obesity and many other widely occurring diseases involve uncontrolled, recurrent bouts of inflammation. In order for us to gain and harness new approaches to treat these diseases and appreciate the complexity of the inflammatory response, it is essential for students, scientists and health care practitioners to command a detailed appreciation of the cellular and molecular language of the inflammatory response, the mediators and governance of this body defense system. The acute inflammatory response is protective, many of the cell types, mediators and mechanisms are known today, and the control of self-limited responses and the progression to natural resolution and tissue homeostasis are beginning to be unraveled. As a major defense mechanism, the innate immune response protects from bacterial invasion and is centered on containment and killing of microbes for their elimination from the body. Hence, the interrelationship between infection and inflammation is a battleground with language that needs to be fully decoded and appreciated in order for us to gain advantage in treatment of diseases where inflammation plays a critical component and hopefully translate into protective practices in personalized medicine. Inflammation and the controlled inflammatory response, namely its resolution, is thus linked to many of life’s processes such as wound healing and aging, while an uncontrolled inflammatory response is viewed today as the instigating mechanism underlying diabetes, neurodegenerative diseases and neuroinflammation and likely many diseases, both sterile injury from within and yet-to-be-described invaders, emphasizing the importance of the inflammatory response and ongoinginflammation as maybe relevant in obesity, metabolic syndrome and aging. The microbiome’s relationship to containment, infection and local tissue inflammation in organs throughout the body remains to be fully decoded, and it is well recognized that the stress of surgery and the local scalpel cut of the surgeon initiate inflammatory responses and potentially (via occlusion of blood vessels with blood reflow),

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injury from within. It is within the spirit of widely appreciating these cellular events, processes and mechanisms that the editors, Drs. Diegelmann and Chalfant, have assembled this eBook containing major contributions from an international distinguished panel of experts to present a didactic experience of the basic cell biology as well as clinical aspects of inflammation. The chapters are by authorities and leading investigators and systematically introduce the cellular and molecular initiators and defenders in the acute inflammatory response and go on to include chapters on inflammation in metabolism, aging, allergy, diabetes, cardiovascular, arthritis, oral disease, gastrointestinal and neural inflammation in well-illustrated and clearly presented didactic chapters. Inflammation when presented in medical school is usually a component of general pathology, or immunology, and in some cases microbiology as well as each of the medical specialties in small bites. Thus, in many respects, the presentation of the innate immune response and its communication to acquired immunity is fragmented in the traditional medical curriculum. This ebook helps to provide, in one succinct presentation, a cohesive view of our multidisciplinary appreciation of inflammation today and how it impacts many disease processes and organs throughout the body. The editors have also taken care to present current approaches in pharmacotherapy in inflammatory responses as well as the application of mathematical modeling and network analysis to inflammation. These are valuable and can help provide a strong foundation to the readers for appreciating the role of inflammation and its treatment for both personalized and precision medicine. This eBook on Basic Biology and Clinical Aspects of Inflammation should be of wide interest across disciplines to not only practitioners, health care providers and basic medical scientists, but should also be of interest to the pharmaceutical and cosmetic industries as well as nutrition and economists, because of the tremendous economic burden of diseases where uncontrolled inflammation is a key culprit. Drs. Diegelmann and Chalfant give us a well-integrated eBook and chapters that will enable the reader to increase our present understanding and gain insight to discover new means to marvel and control this important life process.Inflammation is all!

Charles N. Serhan Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur (HIM 829) Boston, MA 02115, USA [email protected]

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PREFACE In recent years, there have been many exciting advances made in the field of inflammation. State of the art scientific technologies have helped make these advances possible. As underlying cellular and biochemical mechanisms responsible for the inflammatory response are better understood, new therapeutic strategies can be developed to treat the spectrum of clinical problems associated with excessive inflammation. This educational eBook, “Basic Biology and Clinical Aspects of Inflammation” was developed for a wide audience. Basic scientists, academicians, clinicians, health care regulators, industrial and pharmaceutical scientists as well as the lay public can benefit from the expanse of knowledge presented herein. To help continue promoting cutting edge scientific research and technology, the Editors and all contributing Authors have agreed to donate their royalties from this eBook to the Wound Healing Foundation (http://www.woundhealingfoundation.org) for young investigator research grants. In addition, we recognize and appreciate Bentham Science Publishers for their generous support and contributions to the Wound Healing Foundation. Dedication: We dedicate this book to our wonderful wives, Penny and Laura and our loving children, Sarah, Laura, Ryan, Stephen, Scott, Isabella, and Alec.

Robert F. Diegelmann & Charles E. Chalfant Department of Biochemistry and Molecular Biology Virginia Commonwealth University Medical Center 1101 East Marshall Street Sanger Hall, room 2-007 Richmond Virginia, 23298-0614 USA [email protected] [email protected]

iv

List of Contributors Agbor Ndip

Centre for Endocrinology and Diabetes, Institute for Human Development, University of Manchester, Manchester, UK Department of Diabetes, Warrington General Hospital, Warrington, UK

Alastair G. Stewart

Department of Pharmacology & Therapeutics and Lung Health Research Centre, University of Melbourne, Parkville, Victoria 3010, Australia

Alexander A. Karakashian

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA

Andrew J.M. Boulton

Centre for Endocrinology and Diabetes, Institute for Human Development, University of Manchester, Manchester, UK Department of Diabetes and Medicine, Manchester Royal Infirmary, Manchester, UK

Angela M. Reynolds

Department of Mathematics and Applied Mathematics, Virginia Commonwealth University, Richmond, Virginia, USA

Bruce D. Spiess

Johnson Institute for Critical Care research, Department of Anesthesiology, Emergency Medicine, VCU Medical Center, Richmond, Virginia, USA

Chang-An Guo

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA

Chao Li

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond VA, USA

Charles E. Chalfant

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, 23298, USA Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia, 23249, USA The VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, 23298, USA VCU Johnson Center, Virginia Commonwealth University, Richmond, Virginia, 23298, USA VCU Institute of Molecular Medicine, Richmond, Virginia, 23298, USA

Daipayan Banerjee

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA

Dayanjan S. Wijesinghe

Department of Pharmacotherapy & Outcomes Sciences, Virginia Commonwealth University School of Medicine, Richmond, Virginia, 23298, USA VCU Johnson Center, Virginia Commonwealth University, Virginia, 23298, USA

v

Edward B. Jude

Centre for Endocrinology and Diabetes, Institute for Human Development, University of Manchester, Manchester, UK Department of Diabetes, Tameside General Hospital, Ashton-Unde-Lyne, UK

Graham A. Mackay

Department of Pharmacology & Therapeutics and Lung Health Research Centre, University of Melbourne, Parkville, Victoria 3010, Australia

James M. Ntambi

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA

Jennifer A. Mietla

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, 23298, USA

John F. Kuemmerle

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, VCU Program in Enteric Neuromuscular Sciences, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond VA, USA

Joshua L. Kennedy

Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

L. Alexis Hoeferlin

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, 23298, USA

Laura Bond

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA

Lisa J. Gould

Wound Recovery & Hyperbaric Medicine Center, Kent Hospital, Warwick, Rhode Island, USA

Luisa A. DiPietro

Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, IL, USA

Mariana N. NikolovaKarakashian

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA

Mary Elizabeth Hanley

Wound Recovery & Hyperbaric Medicine Center, Kent Hospital, Warwick, Rhode Island, USA

Matthew C. Bell

Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

Matthias Geyer

Department of Rheumatology and Clinical Immunology, Internal Medicine and Rheumatology, Kerckhoff-Klinik, Justus-Liebi-University Gieβen, Bad Nauheim, Germany

vi Megan E. Schrementi

Department of Biological Sciences, DePaul University, Chicago, IL, USA

Praveen R. Arany

Oral Biology, School of Dental Medicine, University at Buffalo, New York, USA

Rebecca A. Segal

Department of Mathematics and Applied Mathematics, Virginia Commonwealth University, Richmond, Virginia, USA

Robert F. Diegelmann

Department of Biochemistry and Molecular Biology and the VCU Johnson Center, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA

Roger M. Loria

Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA

Steffen Gay

Department of Rheumatology, Center of Experimental Rheumatology, University of Zürich, Zürich, Switzerland

Tomasz Arodz

Department of Computer Science, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA

Ulf Müller-Ladner

Department of Rheumatology and Clinical Immunology, Internal Medicine and Rheumatology, Kerckhoff-Klinik, Justus-Liebi-University Gieβen, Bad Nauheim, Germany

Unsong Oh

Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

Xi Gao

Department of Computer Science, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA

Frontiers in Inflammation, 2016, Vol. 1, 3-10

3

CHAPTER 1

Introduction to Basic Biology and Clinical Aspects of Inflammation Roger M. Loria1,*, Robert F. Diegelmann2 Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA 1

Department of Biochemistry and Molecular Biology and the VCU Johnson Center, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA 2

Abstract: Abstract: Inflammation has been recognized as biological phenomena for more than 2000 years by the Roman physician Aulus Cornelius Celcus who described the four cardinal signs of inflammation heat (calor), redness (rubor), pain (dolour), and swelling (tumour), a fifth sign, the loss of function was added later [1]. Consequently, there is ample literature on this subject as illustrated by the fact that more than 500,000 publications on this subject are listed in PubMed. Nevertheless, this volume provides new relevant information on the topic of inflammation, demonstrating that we have not yet complete knowledge on this subject. The reader is directed to extensive introduction of the subject of inflammation [2] as well as many other reports which deals with this subject [3 - 10]. This introductory chapter provides a brief summary of the individual chapter contain in this book.

Keywords: Acute and Chronic Inflammation, Systemic Inflammatory Response Syndrome (SIRS), Cell and Biochemical Mediators, Wound Healing, Metabolism and Aging, Allergy, Diabetes, Cardiovascular, Arthritis, Oral and Gastrointestinal, Neuroinflammation, Pharmacotherapy, Math Modeling and Network Analysis . INTRODUCTION The inflammatory response is classified into the following categories: Address correspondence to Roger M. Loria: Department of Microbiology and Immunology, PO Box 980678, Virginia Commonwealth University, Richmond, VA 23298-0678, USA; Tel: 804-828-9729; Fax: 804-828-9946; Email: [email protected] *

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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Acute Inflammation: is defined as a localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissue. Chronic Inflammation: is defined as prolonged and persistent inflammation marked chiefly by new connective tissue formation; it may be a continuation of an acute form or a prolonged low-grade form. Systemic Inflammatory Response Syndrome (SIRS): is defined as a generalized inflammatory response with vasodilation of capillaries and post capillary venules, increased permeability of capillaries, and hypovolemia. Depressed cardiac function and decreased organ perfusion follow. The various initiating stimuli include sepsis and septic shock, hyperthermia, pancreatitis, trauma, snake bite and immune-mediated diseases [11, 12].

neutrophils 1st responders

Phagocytosis

Phagocytes: neutrophils then macrophages

interleukin-enhances immune response

adhesion molecules adherance margination diapedisis

mast cell degranulation

Macrophage

chemotaxis

TNF

bac pa t teria hog ens Complement

Trauma

Cell Injury

Edema

opsonization cell lysis

Activation of plasma

Vasodilation

systems

Fibrin clots Epithelial Cells

Pain Mast cell

arachidonic acid

TNF Histamine

Leukotrienes

cyclo oxygenase

prostaglandins

Fever

Perrmeability

Fig. (1). Overview of the basic inflammatory cells and mediator responses in tissues following trauma.

Introduction

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An abbreviated schematic of the inflammatory process is provided in (Fig. 1). This tome further illustrates that Inflammation is both a blessing [13] and a curse [14] and both are described in the following chapters. CHAPTER 2 Cell Mediators of Acute Inflammation. Phagocytic cells, including neutrophils and macrophages, produce cytokines that promote inflammation, but are also important for the clearance of microbes and apoptotic cells. This chapter reviews the key functions of these cells in response to an acute insult. CHAPTER 3 Biochemical Mediators of Inflammation and Resolution. Some biochemical mediators are specifically pro-inflammatory or pro-resolution, while others perform both functions. These biochemical mediators play key roles and thus the production and inhibition of these inhibitors are often targets for pharmaceutical intervention. CHAPTER 4 Wound Healing and Dermatologic Aspects of Inflammation. The chapter examines the normal inflammatory response as well as the factors that lead to chronic non-healing wounds. Identification of abnormal cellular and molecular immune responses may lead to targeted therapeutic strategies that promote harmony in the wound healing symphony. CHAPTER 5 Metabolic Regulation of Inflammation. Addresses the metabolic control of inflammation and immunity as well as the molecular aspects of metabolic inflammation converging to insulin resistance.

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CHAPTER 6 Aging and inflammation. Inflammaging is a term referring to the constitutive low-grade inflammation that underlies the process of aging. The inflammaging is considered the main contributing factor to the development of various aging-associated diseases, including cancer, atherosclerosis, metabolic and neurodegenerative diseases. CHAPTER 7 Allergic Inflammation. This chapter provides a description of the various cell types involved in allergic inflammation and the inflammatory responses leading to allergy, including innate and adaptive immunity, are presented in this chapter. CHAPTER 8 Inflammation in Type 2 diabetes. An overview of the key inflammatory mediators and signalling pathways driving the onset of diabetes (beta cell failure and insulin resistance) and the development of complications is presented in this chapter. CHAPTER 9 The Vascular Tree and Heart with Relationship to Inflammation. Deals with the dynamic interactions of endothelium, coagulation and inflammation with a focus upon how perturbations of these systems play in creating disease. CHAPTER 10 Rheumatoid and Degenerative Arthritis-Associated Inflammation. Gives a selected overview over the current knowledge about rheumatoid and degenerative arthritis with a focus on shedding light on the etiopathogenic context

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including establishment of inflammation in both entities. CHAPTER 11 Inflammation in Oral Disease This Chapter discusses the fact that the oral cavity is a unique environment that is subjected to a continuous barrage of physical, chemical and microbial injuries that result in ongoing low levels of inflammation. Perturbation of normal pathophysiological processes results in infections, tissue damage and compromised functions that need to be causally addressed. Managing inflammation in oral tissues is a critical component of oral care and more research is critical in this area to ensure effective clinical management of oral diseases. CHAPTER 12 Intestinal Inflammation and Inflammatory Bowel Disease The combined effects of genetic polymorphisms and dysbiosis combine to result in altered activation and regulation of the intestine’s innate immune and adaptive immune systems that result in sustained inflammation are reviewed. The advances that have elucidated the complex alterations and interactions that shape the inflammatory response of the intestine in the setting of inflammatory bowel disease are highlighted. CHAPTER 13 Neuroinflammation. This chapter outlines the basic mechanisms relevant to central nervous system (CNS) inflammation. The cells of the CNS innate immune response, including microglia, astrocytes, their mechanisms of activation and innate effector mechanisms such as the production of reactive oxygen and nitrogen species and cytokines are discussed. Features unique to the CNS such as the blood-brain barrier and other mechanisms of CNS immune privilege are outlined. Cells and mechanisms of CNS adaptive immune response such as T lymphocytes, Blymphocytes, activation and effector mechanisms are discussed.

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CHAPTER 14 Pharmacotherapy for Inflammatory Processes. Drugs that dampen acute and chronic inflammation and their sequelae are currently some of the most widely utilized therapeutic agents. With the increasing appreciation that inflammation is involved in the pathobiology of most of the serious and complex disorders that affect mankind, the development and therapeutic uses of anti-inflammatory drugs will likely grow with increasing demand for precision interventions in inflammatory pathways. In this article, we examine commonly utilized anti-inflammatory drugs with a view to how their efficacy has informed our fundamental understanding of inflammatory mediators and pathways. We then look at more recently developed, or developing, targeted strategies that have emerged from a deeper appreciation of these pathways. Throughout, utility and limitations of these agents will be discussed with a view to what anti-inflammatory drugs of the future might look like. CHAPTER 15 Mathematical Modelling of Inflammation. Mathematical modelling has been used to investigate the body’s dynamic response to inflammation within the context of a wide variety of conditions and diseases. CHAPTER 16 Network Analysis of Inflammation. An overview of network analysis methods that serve two goals related to detection of biological networks relevant to measured experimental profiling data. Fig. (2) provides an overview of the topics covered in this book.

Introduction

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  Fig. (2). Overview of the topics covered in this book.

CONFLICT OF INTEREST The authors confirm that they have no conflict of interest to declare for this publication. ACKNOWLEDGEMENTS The Editors and Author wish to thank Dr. Michael Maceyka of the Department of Biochemistry and Molecular Biology for his copy-editing assistance for the preparation of this publication. REFERENCES [1]

Rather LJ. Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus. Bull N Y Acad Med 1971; 47(3): 303-22. [PMID: 5276838]

[2]

Kumar Vinay, Abbas Abul K, Aster Jon C, Eds. DInflammation and repair inflammation and repair, chapter 2. In Robbins Basic Pathology. Elsevier Saunders Philadelphia Pa. -9th 2013.

[3]

Khan FA, Khan MF. Inflammation and acute phase response Int J Appl Bio Pharmaceut Tech 2010; 312-20.

[4]

Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454(7203): 428-35. [http://dx.doi.org/10.1038/nature07201] [PMID: 18650913]

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[5]

Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140(6): 821-32. [http://dx.doi.org/10.1016/j.cell.2010.01.040] [PMID: 20303873]

[6]

Farzaneh-Far A, Rudd J, Weissberg PL. Inflammatory mechanisms. Br Med Bull 2001; 59: 55-68. [http://dx.doi.org/10.1093/bmb/59.1.55] [PMID: 11756204]

[7]

Pistikopoulos Efstratios N, Georgiadis Michael C, Dua Vivek, et al. Dynamic models of disease progression: Toward a multiscale model of systemic inflammation in humans. Per Med 2010; 7: 54959. [PMID: 21339856]

[8]

Vodovotz Y, Constantine G, Faeder J, et al. Translational systems approaches to the biology of inflammation and healing. Immunopharmacol Immunotoxicol 2010; 32(2): 181-95. [http://dx.doi.org/10.3109/08923970903369867] [PMID: 20170421]

[9]

Valeyev NV, Hundhausen C, Umezawa Y, et al. A systems model for immune cell interactions unravels the mechanism of inflammation in human skin. PLOS Comput Biol 2010; 6(12): e1001024. [http://dx.doi.org/10.1371/journal.pcbi.1001024] [PMID: 21152006]

[10]

Mi Q, Li NY, Ziraldo C, et al. Translational systems biology of inflammation: potential applications to personalized medicine. Per Med 2010; 7(5): 549-59. [http://dx.doi.org/10.2217/pme.10.45] [PMID: 21339856]

[11]

Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005; 365(9453): 63-78. [http://dx.doi.org/10.1016/S0140-6736(04)17667-8] [PMID: 15639681]

[12]

Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41(2): 580-637. [http://dx.doi.org/10.1097/CCM.0b013e31827e83af] [PMID: 23353941]

[13]

Chandrasoma P, Taylor CR. Part A. general pathology, section II. The host response to injury, chapter 3. Concise Pathology . (3rd ed.), New York, N.Y: McGraw-Hill 2005.

[14]

Kreeger K. Inflammation’s Infamy. Scientist 2003; 28-30.

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CHAPTER 2

Cell Mediators of Acute Inflammation Luisa A. DiPietro1,*, Megan E. Schrementi2 Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, IL, USA 1

2

Department of Biological Sciences, DePaul University, Chicago, IL, USA Abstract: The acute inflammatory response that occurs due to tissue injury or infection involves multiple cell types with both overlapping and specific functions. The resident mast cell is an important sentinel and able to rapidly release proinflammatory mediators via degranulation. Phagocytic cells, including neutrophils and macrophages, produce cytokines that promote inflammation, but are also important for the clearance of microbes and apoptotic cells. Importantly, macrophages also provide substantial reparative signals to direct the healing process once the inflammatory insult is cleared. Other cells that may mediate acute inflammation include epithelial cells and lymphocytes. This chapter reviews the key functions of these cells in response to an acute insult.

Keywords: Cytokines, Inflammation, Innate immunity, Macrophages, Mast cells, Monocytes, Neutrophils, Phagocytosis. INTRODUCTION Acute inflammation, a process that begins within seconds of damage, is a short term process that quickly resolves over hours to days as the insult is removed and tissue is repaired [1]. The cells that are critical to acute inflammation are typically those of the innate immune system. In contrast to adaptive, or specific immune cells (such as lymphocytes), innate immune cells are able to recognize a broad range of microbes and danger-related signals and respond quickly. Address correspondence to Luisa A. DiPietro: Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, IL, 60612, USA; Tel: 312-355-0432; Email: [email protected]

*

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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Acute inflammation is a short term event that ends when the pathogen or foreign particles are removed. By comparison, chronic inflammation involves both innate and adaptive, or specific, immune cell types, and is generally distinguished by a situation where the insult cannot be removed. In some disease states, such as rheumatoid arthritis, tuberculosis, or liver fibrosis, a chronic inflammatory condition persists for years. This chapter describes the types of immune cells that initiate and execute the acute inflammatory process. Acute inflammation is initiated by specialized immune cells that reside in tissues and serve as sentinels for damage or infection. These sentinel cells include resident mast cells, macrophages, and certain nonimmune cells. Sentinel cells identify injury or microbes via specific surface receptors called pattern recognition receptors (PRRs) [2, 3]. PRRs recognize molecules that are commonly found on pathogens (but not normal host cells), as well as molecules that are exposed when tissue is damaged. The activation of PRRs triggers sentinel cells to action, including the release of mediators that attract additional immune cells and further stimulate the acute inflammatory response. Many of the mediators that are released are members of the cytokine family, an important group of proteins that allows cells to signal to one another via interaction with receptors. Other mediators include small molecules such as nitric oxide and eicosanoids. The acute inflammatory response is designed to quickly clear the foreign agent or damaged cells, allowing for tissue repair and resolution of the condition. In addition to the cell types described below, certain cells that are not of immune lineage may also contribute to an acute inflammatory response. For example, epithelial cells can respond to damage as well as to inflammatory mediators by producing cytokines that stimulate the immune response. Other “non-immune” cells that can spur inflammation via the production of cytokines include endothelial cells and connective tissue cells such as adipocytes and fibroblasts [4, 5]. While this chapter focuses on cells of immune lineage, non-immune cells can be important regulators of the acute immune response in certain disease states. As the inflammatory insult is cleared, the acute response resolves. Levels of proinflammatory mediators drop as do the numbers of acute inflammatory cells in the tissue. The process of resolution also involves the active production of mediators

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that resolve inflammation; this process is described further in Chapter 3. Toll-like Receptors Toll like receptors (TLRs) are a group of molecules that are present on many immune cells such as macrophages, neutrophils and dendritic cells. They are among the first molecules to respond to a breach in immune protection. The presence of TLRs on the cell surface allows the immune system to sense the attack of foreign invaders and begin to coordinate an appropriate host response. TLRs recognize small segments of pathogens also known as Pathogen Associated Molecular Patterns (PAMPs). To date, there are nine known TLR s. Those found on the cell surface (TLR 1, 2, 4-6) recognize bacterial and fungal components. Intracellular TLRs recognize viral double-stranded RNA (TLR-3), viral singlestranded RNA (TLR-7 and 8) and bacterial DNA (TLR-9) [6]. In the skin, TLRs 2 and 4 are the most abundant and are found on the surface of keratinocytes, fibroblasts, Langerhans cells, macrophages and mast cells [7]. Although TLRs do not normally recognize most host molecules, they can interact with ligands produced by injured or damaged cells [8]. Thus, TLR’s present on the surface of sentinel skin cells provide a recognition system for tissue damage and possible infection. When a TLR on the surface of a cell binds with its cognate PAMP, a conformational change occurs which results in a complex signaling cascade within the cell. The result of the signaling differs depending on the TLR ligand interaction. For example, when LPS, a component of gram-negative bacteria, binds to and is recognized by TLR4, the signaling cascade leads to the production of proinflammatory cytokines that can attract more cells to the area to control a possible infection. Mast Cells Mast cells are relatively large, granule filled cells that are found throughout many tissues in the body. Mast cells were first identified more than 100 years ago by the German Nobel awardee, Paul Ehrlich, who named them mastzellen from the German word mast, to indicate their “fat” appearance [9]. Tissue bound mast cells derive from immature progenitors, and become fully developed and filled with

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granules only after they enter tissues. The granules consist of preformed mediators such as cytokines and vasoactive amines. These granules are released upon activation and allow a quick immune response to be initiated. Mast cells exhibit a high level of heterogeneity, and vary both in amount of mediators produced and responses to specific stimuli [10]. High levels of mast cells are typically seen at surfaces that are directly exposed to external stimuli such as the lungs, gastrointestinal tract, mouth, and skin [11]. This localization makes the mast cell a particularly important as a first responder to external insults. During an inflammatory response, the numbers of mast cells at the site may transiently increase as mast cells migrate from adjacent tissue into the site of inflammation. Mast cells respond to stimuli by undergoing degranulation, a process by which a large variety of preformed mediators are released from their granules. In addition, mast cells may actively produce cytokines and inflammatory molecules in response to stimuli. Triggers of Mast Cell Degranulation Mast cells can be activated by a variety of different stimuli including those derived from allergy or trauma [11]. In regard to the allergic response, this process is well described in Chapter 7, Allergic Inflammation. In brief, mast cells carry high-affinity receptors for the constant region of IgE, the immunoglobulin class that is the culprit of allergic inflammation [12]. IgE binds these mast cell receptors, and mast cells are thus coated with IgE. In non-allergic situations, the receptors filled with IgE remain inactive. However, in persons with IgE mediated allergy, mast cells can become coated with IgE directed against the allergen. If an exposure to the allergen occurs, surface IgE becomes cross-linked, stimulating a signaling cascade that leads to mast cell activation and degranulation. While this function of mast cells has been widely studied in terms of allergic reaction, this response may also be important in the immune and inflammatory response to parasitic infections, some of which evoke an IgE response. The activation of mast cells by allergens and the subsequent release of a large amount of vasoactive amines can create a life-threatening situation. Because of this, the response of mast cells to IgE has received a good deal of experimental attention. The mast cell role goes well beyond allergic and parasitic diseases,

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though, as mast cells can be activated by many other stimuli in addition to those that activate via IgE [13]. Mast cells may degranulate in response to thrombin, a molecule produced whenever the vasculature is breached. Mast cells also respond to the complement fragments C3a and C5a via specific receptors. Like many innate immune cells, mast cells are able to recognize common molecular motifs on microbes via Pattern Recognition Receptors (PRRs) [14]. Finally, non-specific stimuli, including pressure, heat and cold, may lead to mast cell degranulation [15]. Thus there are multiple paths by which mast cells detect dangerous events and are induced to undergo degranulation and activated to secrete mediators, with the end result of eliciting an inflammatory response. Mediators Released by Mast Cells The mediators that are released by mast cells include preformed molecules that are stored in granules and those that are synthesized following activation [14]. The release of preformed mediators via degranulation is a rapid process that occurs via a Ca++ dependent exocytosis. Preformed mediators that are released by mast cells consist of several serine proteases (e.g. tryptase, chymase), vasoactive amines, and cytokines/growth including VEGF, TNFα, and FGF2. The vasoactive amines, of which the most functionally prominent may be histamine, cause dilation and increased permeability of the vasculature and constriction of smooth muscle. This increased permeability will allow circulating immune cells to enter the injured area to respond to and control infection. Locally, these effects lead to edema; in the lung, bronchiolar constriction may also result. Beyond the rapid release of preformed mediators from granules, the activation of mast cells induces active synthesis of pro-inflammatory molecules. Inflammatory lipid molecules, including leukotrienes and prostaglandins, are produced by activated mast cells via the arachidonic acid pathway. More than 20 different inflammatory cytokines have also been described to be synthesized by mast cells following activation. In contrast to the quick release of the premade molecules stored in the granules, production of cytokines via mast cell activation occurs by transcriptional activation and resulting protein synthesis.

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NEUTROPHILS Neutrophils are the most abundant white cell in humans, and play a critical role in acute inflammation [16]. Neutrophils form in the bone marrow and are released in mature form. Within the circulation, neutrophils have a relatively short half-life of about five days, and in health, they rarely exit the blood stream. Yet when an inflammatory insult occurs, neutrophils are able to mobilize very quickly and can enter the site of injury within minutes. Neutrophil recruitment, similar to the recruitment of almost any circulating leukocyte, involves the sequential steps of endothelial cell activation, recognition of the activated endothelium by the circulating cell, cell-to-cell interaction, and active migration through the endothelium into the extravascular space [17]. The neutrophil has specific receptors than allow it to follow a path of chemotactic signals such as activated complement components and chemotactic cytokines released by the activated sentinel cells; these signals direct the neutrophil through the endothelium and towards the inflammatory site. Once within the tissue, neutrophils contain an arsenal of weapons that allow them to destroy most microbes. They are part of the phagocytic lineage of immune cells, a lineage in which ingestion of particles is a common mechanism of pathogen clearance. Neutrophils kill pathogens by ingestion via phagocytosis and by trapping microbes in extracellular nets [18]. During phagocytosis, microbes are recognized by surface receptors that recognize common microbial molecular motifs. In a process called opsonization, phagocytosis can be greatly enhanced if microbes are coated with antibody or activated complement, as neutrophils have high affinity receptors for these molecules. Following recognition, particles are engulfed by the neutrophil into an intracellular membrane bound vesicle termed a phagosome. The phagosome then fuses with lysosomes, creating a phagolysosome. The phagolysosome is a hostile environment in which reactive oxygen species (ROS) are created and enzymatic activity occurs. The generation of ROS requires oxygen, and the use of oxygen during the phagocytic process has been called the respiratory burst. Large amounts of superoxide are produced in the phagolysosome by the activation of NADPH oxidase. Superoxide is broken down to hydrogen peroxide, which is further converted to HOCL by myeloperoxidase. Each of the reactive oxygen species may contribute to the killing of microbes

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within the phagolysosome. Phagolysosomes also contain additional elements that support microbial destruction, including proteases and anti-microbial peptides. The end result of the phagocytic process is microbial death and digestion. In contrast to phagocytosis, extracellular killing of microorganisms can occur when activated neutrophils release a web of DNA that surrounds the microbe. NETs, or neutrophil extracellular traps, are composed of DNA and proteases and lead to microbial death. NETs are believed to create an environment that is rich in anti-microbial agents, but may also represent a physical barrier that prevents microbial movement [19]. Neutrophils can be induced to form NETs by a variety of cytokines and chemokines, and it has been shown that NADPH oxidase and myeloperoxidase may be involved in the production of NETs in at least some situations [20]. One important consequence of neutrophilic activity is the extracellular release of mediators contained within the granules. While granular contents that fuse with the phagolysosome remain internal to the neutrophil, frequently some granular contents are released into the extracellular space. The release of reactive oxygen species, proteases, and other active compounds can lead to destruction of normal cells in the area, an event called bystander destruction. As clearance of the pathogen and necrotic tissue winds down, the neutrophils that have entered the site must themselves be cleared. Senescent and apoptotic neutrophils at sites of inflammation exhibit a range of markers that make them susceptible to apoptosis by macrophages. This active clearance of neutrophils is believed to be important to the resolution of inflammation and the restoration of tissue homeostasis [20]. MACROPHAGES Macrophages represent a cell type that has great diversity of function and many phenotypic variations of this cell type have been described [21]. Macrophages are phagocytes, and derive from the same precursor as neutrophils. Distinct from neutrophils, however, most macrophages reside within the tissue, as the mature cell is not normally found in circulation. Subsets of the macrophage lineage may bear characteristics specific to their tissue location, and macrophages at specific

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site are frequently referred to by specific names that derive from both function and histologic appearance (Table 1). The commonality among these subsets of tissue resident macrophages is their ability to respond to invading pathogens, inflammatory mediators, and tissue destruction to contain the insult and further the appropriate inflammatory response. Table 1. Tissue Resident Macrophages. Macrophage Name

Location

Adipose tissue macrophages

Adipose tissue

Monocyte/immature macrophage

Bone marrow and blood

Kupffer cell

Liver

Sinus histioctyes

Lymph node

Alveolar macrophages

Lungs

Tissue macrophage

Connective tissue

Langerhans cell

Skin and mucosa

Microglia

Central nervous system

Hofbauer cell

Placenta

Intraglomerular mesangial cell

Kidney

Osteoclasts

Bone

Red Pulp Macrophage

Spleen

Peritoneal macrophages

Peritoneum

While the overall macrophage levels in normal tissue appear static, turnover of these cells does occur, albeit slowly. During acute inflammation, though, macrophage content in tissues generally increases substantially. This increase is largely dependent upon the movement of circulating monocytes into the tissue; monocytes then mature into functional macrophages. Recent evidence also suggests that macrophages have the capacity for self-renewal within tissues, and the contribution of self-renewal versus monocyte derivation to the increase in macrophages during inflammation requires further investigation [22]. Fig. (1) depicts a summary of the innate immune response to tissue injury. Macrophage Function and Phenotypes Macrophages can respond to their environment by developing phenotypes that

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support either the generation or resolution of inflammation [23]. The specific phenotype depends upon the factors to which the cell is exposed (Fig. 2). Resident macrophages in tissue are quickly stimulated during the initial inflammatory response to become more actively phagocytic and to produce a variety of proinflammatory mediators.

Fig. (1). A summary of the innate immune response to tissue damage. When the tissue is broken, bacteria, viruses or debris may enter. Blood platelets initiate clotting while mast cells begin to degranulate. Degranulation of mast cells releases histamine and cytokines. This release attracts neutrophils and macrophages to the site of damage where pathogens are phagocytosed. The macrophages eventually change their phenotype to secrete cytokines involved in tissue repair.

Exposure to a wide range of factors, including microbial molecules, activated complement, interferons, and other cytokines causes macrophages to move from a relatively inactive state into an activated proinflammatory phenotype. The activated and inflammatory state has been dubbed the M1 macrophage (Fig. 2). M1 macrophages

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produce a large number of mediators and cytokines that enhance the inflammatory response by 1) activating endothelium, 2) serving as chemoattractants that recruit additional leukocytes, and 3) stimulating phagocytosis and other cellular processes that eliminate the inflammatory insult. M1 macrophages are also highly phagocytic and remove microbes and other particles in a process quite similar to that described for neutrophils, above.

Fig. (2). Macrophage phenotypes and functions. Macrophages exhibit a wide range of different functional capacities. Many in vitro studies suggest that macrophages fall into discrete phenotypes, such as those depicted here (M1 and M2). However, emerging evidence supports that idea that macrophages actually take on a large variety of intermediary phenotypes in vivo.

As inflammation resolves, macrophages respond by converting from the M1 proinflammatory phenotype to a reparative, wound healing phenotype termed an M2 macrophage. The M2 macrophage expresses anti-inflammatory mediators, and is also characterized by the production of growth factors that support tissue repair [17]. In point of fact, the switch of macrophages from an M1 to an M2 phenotype involves a continuum of phenotypes; in vivo studies suggest that macrophages at sites of inflammation rarely fall cleanly into the M1 or M2 phenotype. Thus, the use of M1 and M2 (or other phenotypic nomenclature) has been suggested to be highly limiting to our understanding of macrophage function [24]. Dispensing with nomenclature, certain functional elements of macrophage activity in acute inflammation are clear. The macrophage, via modulation of phenotype, is capable

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of sequentially supporting inflammation and then the tissue repair that is needed as inflammation subsides. The macrophage is therefore a critical player in both clearance of pathogens and in wound healing. As inflammation resolves, one important feature of macrophage activity is their ability to remove neutrophils. Macrophages recognize and ingest apoptotic neutrophils, removing them in a process termed efferocytosis [25]. Macrophages have also been described to induce apoptosis in neutrophils, further contributing to the resolution of inflammation. Multiple pieces of evidence suggest that the ingestion of apoptotic neutrophils promotes a phenotypic switch in macrophages to the reparative phenotype as inflammation resolves. Defects in the capacity of macrophages to effectively remove neutrophils have been described to prolong the inflammatory process, inhibiting resolution and tissue repair [25, 26]. The link between the innate and adaptive immune response is provided by cells that can process antigen encountered in the tissue, travel to the lymph tissue and present that antigen to lymphatic T cells. Both macrophages and dendritic cells can act as antigen presenting cells (APCs). Once the surface of an APC is coated with fragments of foreign proteins, APC’s travel to the peripheral lymph tissue, where they present the antigens to T-helper lymphocytes residing there. This process activates antigen specific T-cells to proliferate and produce cytokines to continue the immune response. ADAPTIVE IMMUNE CELLS IN ACUTE INFLAMMATION The acute inflammatory response is dominated by cells of the innate immune system. However, the acute inflammatory response does include some immune cells that are derived from the adaptive immune lineage. In this situation the cells behave as innate immune cells. Two specific examples of this intersection of the adaptive and innate systems are gamma delta T cells and Th17 lymphocytes. Gamma Delta T Cells Gamma delta T (γδT) cells are a complex cell type that is described to bridge adaptive and innate immunity [27]. Derived from the T lymphocytic lineage, a subset of γδT cells that bear a highly restricted T cell receptor reside within

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tissues that are exposed to the environment, including mucosa and skin. Several pieces of evidence suggest resident γδT cells serve as sentinels at sites of injury and can promote acute inflammation. γδT cells can be directly activated by pathogen-associated or danger-associated molecular patterns. At sites of injury, γδT cells secrete effectors that contribute to the acute inflammatory response, including chemotactic and proinflammatory cytokines, defensins, and interferon. These unconventional lymphocytes may often play a role in acute inflammation, but may also take on roles in adaptive immunity via diversification of their T cell receptor and the development of antigen-specific responsiveness. TH17 T Lymphocytes Although T lymphocytes most frequently function strictly within the context of the adaptive immune system, the T helper 17 (Th17) cells are unique in distribution and function. Th17 cells are widely distributed in tissues, and are activated by pathogens and proinflammatory cytokines [28, 29]. Once activated, Th17 cells produce multiple cytokines that enhance host defense at sites of inflammation. Importantly, Th17 cells produce IL-17, an interleukin attracts and stimulates neutrophils. Moreover, IL-17 induces several other cell types to produce cytokines that are chemoattractant for neutrophils. IL-17 also stimulates the production of factors that induce granulopoiesis, a process that leads to the production of more neutrophils in the bone marrow. Functionally, Th17 cells play an important role in generating an effective inflammatory response, particularly to extracellular bacteria [28]. SUMMARY Acute inflammation represents an important physiologic process that is designed to remove foreign agents quickly. The principal cells that mediate acute inflammation are those of the innate immune system, including mast cells, neutrophils, and macrophages. These cells produce a variety of inflammatory and anti-microbial mediators; the cells clear microbial particles and damaged tissue by phagocytosis. The end result of an effective acute inflammatory process is the removal of the offending agent and/or damaged tissue, and the initiation of tissue repair.

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CHAPTER 3

Biochemical Mediators of Inflammation and Resolution Jennifer A. Mietla1, L. Alexis Hoeferlin1, Dayanjan S. Wijesinghe2,5, Charles E. Chalfant1,3,4,5,6,* Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA 1

Department of Pharmacotherapy & Outcomes Sciences, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA 2

Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia 23249, USA 3

The VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA 4

5

VCU Johnson Center, Richmond, Virginia 23298, USA

6

VCU Institute of Molecular Medicine, Richmond, Virginia 23298, USA Abstract: Inflammation is the response of the immune system to injury and infection. As such, it is a critical component of multiple disease states, including anaphylaxis, cancer, cardiovascular disease, obesity, rheumatoid arthritis, diabetes and asthma. Inflammation is a complex process that is composed of multiple stages – the main stages being a pro-inflammatory stage followed by a pro-resolution phase. Eicosanoids and cytokines are critical biochemical mediators involved in both the initiation of the inflammatory response and the resolution of the inflammatory response. Some biochemical mediators are specifically pro-inflammatory or pro-resolution, while others perform both functions. These biochemical mediators play key roles, and thus, the production and inhibition of these mediators are often targets for pharmaceutical intervention. Address correspondence to Charles E. Chalfant: Department of Biochemistry and Molecular Biology, Room 2-016, Sanger Hall, Virginia Commonwealth University, School of Medicine, 1101 East Marshall Street, P.O. Box 980614, Richmond, VA 23298-0614, USA; Tel: 804-828-9526; Fax: 80408281473; Email: [email protected]

*

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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Keywords: Chemokines, Cytokines, Eicosanoids, Inflammation, Phospholipase A2, Resolvins. INTRODUCTION Inflammation can be defined as the body’s immediate response to damage to its tissues and cells by pathogens, noxious stimuli, or physical injury [1], and it can be acute or chronic. It is composed of many coordinated processes (Fig. 1) that are actively signaled by both specific protein and lipid molecules [2]. The first step in the immune response involves inflammation and is characterized by the production of pro-inflammatory mediators, an influx of innate immune cells, and tissue destruction [3]. The resolution of inflammation involves the production of anti-inflammatory mediators, an influx of macrophages, and tissue repair [3]. Eicosanoids are well established mediators of both the initiation and the resolution of inflammation, but there is still much to learn as the roles of only few eicosanoids have been well studied. Additionally, cytokines and chemokines play roles in both the initiation and resolution of inflammation. Inflammation is a critical component of many disease states including anaphylaxis, cancer, cardiovascular disease, obesity, rheumatoid arthritis, diabetes and asthma [4 - 13]. For example, in tumor development, inflammatory responses are involved in infiltration, promotion, malignant conversion, invasion, and metastasis [5]. There is also increasing evidence that prolonged inflammation in the vascular wall results in atherosclerosis [14 - 17]. Another increasing health concern, obesity, is also characterized by an overall inflammatory response in the body, and may impact the ability of the body to utilize insulin effectively [10, 18, 19]. As inflammation is intrinsically involved in multiple disease states, gaining a greater understanding of the mechanisms involved in this process could lead to new strategies for disease treatment and prevention.

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BIOSYNTHESIS OF LIPID MEDIATORS Phospholipase A2 Phospholipases A2 (PLA2s) are enzymes that hydrolyze the sn-2 ester bond of cellular phospholipids to release free fatty acids and, as a result, form lysophospholipids [20, 21]. Pathogens, noxious stimuli, physical injury

Pro-inflammatory Lipid Mediators

Pro-inflammatory cytokines/chemokines

Influx of Innate Immune cells (PMNs)

Acute Inflammation

(Rubor, Calor, Tumor, Dolor)

Pro-resolution Lipid Mediators

Pro-resolution cytokines/chemokines

Influx of Macrophages

Resolution of Inflammation

Fig. (1). General Course of Inflammation. Inflammation is a multi-step process that is actively signaled by specific lipid and protein molecules.

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These lipid mediators may act as either intracellular messengers or leave the cell and interact with neighboring cells [23]. PLA2s were first discovered as a major component of snake venoms at the end of the nineteenth century [24], and since then over 30 enzymes that possess PLA2 activity have been identified [21]. These enzymes have been classified into six groups – 1) the cytosolic PLA2s, 2) the secretory PLA2s, 3) the calcium-independent PLA2s, 4) the platelet activating factor acetylhydrolases, 5) the lysosomal PLA2s, and 6) the adipose-specific PLA2s [22]. This chapter will discuss the three main PLA2 groups that are involved in the inflammatory process – cytosolic, secretory, and calciumindependent PLA2s (Fig. 2).

(A) cPLA2a N

Arg200Ser228

CaLB/C2domain CBR II

CBR I

Ser505

Ser727

P CBR III

P

Catalytic domain Hinge

C Asp 549

PC binding site

C1P binding site

(B) iPLA 2 b

Active Site (S519)

Ankyrin Repeats

N

I

N

CaM binding

C

Patatin domain

II III IV V VI VII

(C) sPLA2 (IIA)

PIP2binding site

PC binding site

H47

Ca2+binding

Catalytic Site

C51

C-term Extension

C

C124

Fig. (2). Structures of the three main PLA2 groups that are involved in the inflammatory process.(A) cPLA2α structure. (B) iPLA2β structure. (C) sPLA2 (IIA) structure.

Group IVA Cytosolic Phospholipase A2 (cPLA2α) cPLA2α was first characterized in platelets and macrophages and was cloned from

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a macrophage cDNA library [23, 25, 26]. Platelets, macrophages, neutrophils, endothelial cells, vascular smooth muscle cells, alveolar epithelial cells, renal mesangial cells, mast cells, and keratinocytes have all been shown to contain cPLA2α [27 - 29]. Studies have also shown that the cPLA2α protein is expressed in the spleen, brain, lung, heart, liver, kidney, and uterus of the mouse [30, 31]. The cPLA2α cDNA encodes for a 749 amino acid protein with a molecular weight of approximately 85 kDa [23]. Several discrete domains have been identified in the cPLA2α protein [23], including the C2/CaLB domain which encodes the Ca2+dependent binding of cPLA2α to membranes [23, 32], the catalytic domain of cPLA2α which includes essential amino acids for catalytic activity (Arg200 and Ser228) [23, 33, 34], the flexible hinge region which has homology to the hinge region of PKC [23, 32]. The subcellular localization of cPLA2α has been examined using immunofluorescence microscopy, and studies have shown that upon activation, cPLA2α translocates to the endoplasmic reticulum, Golgi apparatus, and the nuclear membrane [35, 36]. An additional study has shown that in subconfluent endothelial cells, a portion of cPLA2α appears within the nucleus [23, 37]. Regarding the cleaving activity of cPLA2α, it preferentially cleaves arachidonic acid-containing phospholipids with a preference for phosphatidylcholine (PC) [38]. Activation of cPLA2α in cells (translocation to membranes and induction of AA release) requires an extracellular stimulus, Ca2+, and the C2/CaLB domain [23, 32 - 34]. A wide variety of extracellular stimuli can activate cPLA2α. These stimuli include growth factors, cytokines, interferons, and UV light [23]. Calcium ionophores, such as A23187, also induce a large release of arachidonic acid due to the large increase of intracellular Ca2+ levels [39]. Phosphorylation may also play a role in the regulation of cPLA2α activation, as a variety of extracellular stimuli cause rapid phosphorylation of cPLA2α [23]. Ser505 has been shown to be phosphorylated by ERK and p38 kinases, while Ser727 is phosphorylated by p38activated protein kinases [40 - 42]. Two

anionic

lipids

have

been

demonstrated

to

activate

cPLA2α

–

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phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and ceramide-1-phosphate (C1P). Over the past decade, the Chalfant laboratory has demonstrated a distinct role for ceramide-1-phosphate in regulating cPLA2α activation via a direct interaction between C1P and the C2/CaLB domain of cPLA2α [39, 43 - 50]. C1P increases the membrane residence time of cPLA2α, which enables the enzyme to cleave more arachidonic acid. In contrast, though PI(4,5)P2 has been shown to activate cPLA2α [51 - 53], it activates the enzyme in a different manner than C1P. Specifically, PI(4,5)P2 increases the catalytic efficiency of cPLA2α by increasing both membrane penetration and the rate of substrate hydrolysis [49]. Secretory Phospholipase A2 (sPLA2) Secreted PLA2s have been cloned from humans, mice, and rats [54 - 56]. There are currently 17 different isoforms of sPLA2 identified, with 11 of those expressed in mammalian cells [22]. This enzyme has been detected in P388D1 macrophages, mast cells, platelets, eosinophils, neutrophils, monocytes, and basophils [56 - 59] as well as the heart, lung, placenta, spleen, pancreas, and thymus [56 - 60]. The various sPLA2 isoforms have lower molecular weights than the other phospholipase A2s, typically 14-19 kDa [22]. Structurally, this group of enzymes shares a highly conserved calcium binding region, six conserved disulfide bonds, and a histidine/aspartic acid catalytic dyad [22]. Similarly to cPLA2α, sPLA2s are typically calcium dependent and require millimolar concentrations for optimal function [22]. For this reason, sPLA2s typically are only active extracellularly and will hydrolyze a variety of phospholipids [22], though they tend to prefer those with negatively charged head groups such as phosphatidylserine, phosphatidylglycerol, and phosphatidylethanolamine [22]. In mouse bone marrow derived mast cells, sPLA2 has been shown to be associated with the Golgi apparatus, nuclear envelope, and plasma membrane [61]. Group VIA Phospholipase A2 (iPLA2β) iPLA2 was first identified in P388D cells and macrophages and was then purified, cloned, sequenced, and characterized [62]. This enzyme has also been detected in INS-1 cells [63], pancreatic islet cells [64], insulinoma cells [64], and P388D1 macrophages [65] as well as the heart [65], brain [65], and kidney [65].

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iPLA2β is an approximately 85 kDa protein, and despite a similar molecular weight, it does not have any sequence homology with cPLA2α [66]. It can occur in at least 5 different splice variants with two demonstrating enzymatic activity. These two variants differ only by an interruption of the eight ankyrin-like repeated domain by a proline-rich 54-amino acid stretch [66]. Activation of iPLA2β has been examined in vitro, and has shown that specific activity may be higher in the presence of ATP [66] and that the active species is a tetramer [66]. Intriguingly, studies have demonstrated that in the presence of calcium, calmodulin will bind tightly and inhibit activity of the enzyme [66], and deletion of the ankyrin repeats will also inactivate the enzyme [66]. Eicosanoid Production Pathways Once arachidonic acid is released from cellular phospholipids by the action of a phospholipase A2, it can be metabolized through three main pathways – the cyclooxygenase pathway, the lipoxygenase pathway, and the cytochrome P450 pathway. Each of these pathways convert arachidonic acid to various eicosanoids (Fig. 3). Esterified sn-2 Fatty Acid in Membrane Phospholipids Activation of cPLA2a Free arachidonic acid

Free eicosapentaenoic acid (EPA) COX1/COX2 PGH 3

Lipoxygenases (5-LO, 12-LO, 15-LO)

acetylated COX2/P450 5-LO

PGI 3 TxA3 PGE3

LTA 5 LTB5

18R/S-H(p)EPE 18R/S-Resolvin E1/2

LTA4 LTB 4 LTC4

HETES

Free docosahexaenoic acid (DHA) Lipoxygenases

Cyclooxygenases (COX1/COX2) PGG 2

Lipoxins

Epoxidation

PGH2

15-HETE 5-HETE 12-HETE

Protectin D1

LTD 4 LTE4

Prostacyclins

Acetylated COX 17R Resolvin D

17S Resolvin D

Prostaglandins Thrpmboxanes

PGI 2 6-keto-PGF 1a

LO/LO

TxA 2

PGE2

PGD 2

PGF2a

TxB 2

Fig. (3). General biosynthetic pathways for eicosanoids and 3-PUFA-derived lipid mediators. Red = pro-inflammatory lipid mediators; Green = anti-inflammatory lipid mediators; and Yellow = Reported as both pro- and anti-inflammatory.

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Cyclooxygenase (COX) Pathway The COX pathway consists of two enzymes, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). COX-1 was first purified in 1976 from bovine vesicular glands and is constitutively expressed in a wide variety of tissues including kidney, lung, stomach, duodenum, ileum, and colon [67]. COX-2 was identified in 1989 [68] and, unlike COX-1, is not constitutively expressed in most tissues [69, 70]. Rather, this enzyme is induced via a variety of extracellular and intracellular stimuli including LPS, IL-1, TNF, and EGF [71 - 76]. Induction of COX-2 is transient and will typically return to basal levels within 24-48 hours [67]. Despite these two enzymes having similar primary protein structures and carrying out the same catalytic activity, they are derived from distinct genes [77] and differ in their utilization of arachidonic acid and in mRNA stability [77]. For COX-2, mRNA regulation appears to be an important mechanism used to regulate prostaglandin levels. It has also been demonstrated that COX-2 can utilize arachidonic acid that is already located in cells whereas COX-1 does not have this ability. As previously mentioned, both of these enzymes utilize the arachidonic acid released by phospholipase A2 enzymes to begin the prostaglandin synthetic pathways [60, 78]. The conversion of arachidonic acid into other eicosanoids by the COX enzymes occurs via a two-step process. First, arachidonic acid is converted to PGG2, via introduction of two oxygen molecules. PGG2 is then reduced to PGH2via peroxidation. Next, a variety of synthetic enzymes transform PGH2 into all other prostaglandins, prostacyclin, and thromboxanes [67]. Lipoxygenase Pathway A second pathway composed of six lipoxygenase enzymes can also act upon arachidonic acid to produce a different subset of eicosanoids [79]. These enzymes are found in a wide variety of animals, plants, and fungi [80] and do have a few common structural features. The lipoxygenase enzymes are composed of a single polypeptide chain containing six conserved histidines, an N-terminal β-barrel domain, and a larger catalytic domain. The catalytic domain contains a single

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non-heme iron molecule which is liganded to histidines and to the carboxyl group of an isoleucine at the C-terminus of the protein [80, 81]. The enzymes are approximately 75-80 kDa [80]. In this chapter we will focus on three of the lipoxygenase enzymes – 5-lipoxygenase (5-LO), 12-lipoxygenase (12-LO), and 15-lipoxygenase (15-LO). 5-lipoxygenase has been cloned from a variety of sources, including human, rat, mouse, and hamster [81] and can be found in the placenta, leukocytes, neutrophils, eosinophils, macrophages, mast cells, B-lymphocytes, and dendritic cells [79, 82]. 5-LO will convert arachidonic acid to 5-HPETE which can then be reduced to 5-HETE, or 5-LOX can again act on 5-HPETE and convert it to leukotriene A4 (LTA4). Next, various synthetic enzymes can convert LTA4 into LTB4 or LTC4. LTC4 can be further acted upon to produce LTD4 and LTE4. Regarding activation of 5-LO, the enzyme needs calcium and ATP as well as the assistance of 5-lipoxygenase activating protein (FLAP) [80, 81]. FLAP, an 18 kDa integral membrane protein, assists by presenting arachidonic acid to 5-LO [80]. 12-LO and 15-LO function in similar manners to 5-LO in that they produce 12HETE and 15-HETE. They differ from 5-LO in that they do not require an activating protein like FLAP to perform their function. 12-lipoxygenase converts arachidonic acid to 12-HETE, and this was first demonstrated in the mid-1970s [83]. There are actually two different types of 15-LO – 15-LO-1 and 15-LO-2 [84]. Both types of 15-LO convert arachidonic acid to 15-HETE, though the difference is the location of where the oxygenation occurs. 15-LO-1 will oxygenate arachidonic acid at both C-15 and C-12 [84] while 15-LO-2 oxygenates only C-15 [85]. Cytochrome P450 Pathway A third subset of enzymes, those from the cytochrome P450 pathway, can be utilized to convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs) and epoxytrienoic acids (EETs). This pathway can be divided into two subpathways – the ω-hydrolase and the epoxygenase pathways [86]. A variety of ωhydrolases will produce the various HETE isomers, while epoxygenases are utilized to create various EET isomers from arachidonic acid [87]. The EETs can

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then be further modified into dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolases. PRO-INFLAMMATORY LIPID MEDIATORS Lipid mediators provide a wide variety of functions in the cell and in the body and can function as both pro-inflammatory or pro-resolution/anti-inflammatory. The main lipid mediators which are pro-inflammatory are the leukotrienes (LTB4, LTC4, LTD4, and LTE4) and the HETEs (particularly 5-HETE). The leukotrienes are a class of eicosanoids that are produced via the 5lipoxygenase (5-LO) pathway by a variety of leukocytes. This class of lipids has been demonstrated to play a role in a variety of disease states, including multiple cancer types (e.g. lung, pancreatic, and prostate [88]), peritonitis [89], arthritis [90], airway hyperresponsiveness [91], and ischemia-reperfusion injuries [92]. In humans, the various leukotrienes are produced by different leukocytes in varying amounts, with some cells producing largely one type. For example, neutrophils, B-lymphocytes, monocytes, and macrophages typically produce LTB4, while eosinophils and mast cells largely produce LTC4 [88]. Each of the leukotrienes plays different roles in the immune and inflammatory response. LTB4 is a major pro-inflammatory eicosanoid. It has significant roles in the inflammatory response, varying from recruitment of leukocytes into tissues through chemotaxis, activation of leukocytes, and increasing adherence of leukocytes to the endothelium [88]. As expected, this eicosanoid has been shown to be upregulated in a variety of inflammatory disease states, including rheumatoid arthritis [93], psoriasis [94], Crohn’s disease [95], and cystic fibrosis [96]. The other leukotrienes (LTC4, LTD4, and LTE4) are often grouped together and referred to as the cysteinyl leukotrienes (CysLTs). The members of this group of eicosanoids are well known bronchoconstrictors [88, 91], but are also implicated in vasoconstriction and activation of eosinophils and monocytes [88]. The CysLTs are also major components of asthma and allergy. They affect the production of chemokines by mast cells and also increase proliferation of mast cells [91, 97]. LTE4 is particularly potent in this regard [91]. The CysLTs are also intricately

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involved in edema that is characteristic of allergic reactions as they act on epithelial cells to allow leaking of plasma into tissues [88]. LTC4 and LTD4 are rapidly metabolized into LTE4, which is therefore the most abundant cysteinyl leukotriene when levels are measured in biological fluids [97]. Interestingly, in one study, LTE4 was demonstrated to induce the accumulation of both eosinophils and basophils in the bronchial submucosa of mild asthmatic subjects, while LTD4 was unable to do so [97]. 5-HETE is another eicosanoid that plays a pro-inflammatory role and is produced by human neutrophils, eosinophils, monocytes, lymphocytes, and macrophages [98]. It is particularly effective in regard to neutrophil activities. Studies have demonstrated that 5-HETE is a potent neutrophil aggregating agent” [99, 100], and is involved in chemokinesis, chemotaxis, and mobilization of intracellular calcium levels in neutrophils [101]. 5-HETE also will be rapidly incorporated into cellular lipids in PMNs [101]. 5-HETE can be transformed into 5-oxo-ETE [101], which serves as a potent eosinophil chemoattractant [102]. This eicosanoid also has multiple functions, including chemokinesis in eosinophils [102], as well as being involved in both chemotaxis and inducing intracellular calcium mobilization in neutrophils [103]. 5-HETE also plays a role in anaphylaxis and other disease states that involve the airway. It has been shown to be upregulated in human airways after anaphylaxis in high enough levels to increase mucus secretion [98]. It will also induce bronchial smooth muscle contraction and enhance antigen-induced histamine release from human basophils [98]. In regard to neutrophil chemotaxis, one study demonstrated that 5-HETE will induce human neutrophil migration across naked filters and endothelial (HUVEC) and epithelial (A549) barriers in a dose- and time-dependent fashion [98]. Intriguingly, some eicosanoids play both pro-inflammatory and pro-resolution roles. These include PGE2, PGD2, PGF2α, PGI2, TXA2, and TXB2. Of this group of eicosanoids, PGE2 is the most widely studied. Regarding pro-inflammatory roles, PGE2 has been shown to play a role in rheumatoid arthritis and atherosclerosis [104]. PGE2 regulates multiple cell types, including dendritic cells, T-cells, B cells, and macrophages [104]. PGD2, an isomer of PGE2, is produced in the central nervous system and

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peripheral tissues, and by mast cells, dendritic cells, and Th2 cells [104]. PGD2 plays a variety of physiological roles, including bronchoconstriction and eosinophil infiltration in asthma and increased allergic response in ovalbumininduced airway hyperresponsiveness [104]. PGI2 regulates cardiovascular homeostasis [104], and thus many vascular cell types produce PGI2, including endothelial cells, vascular smooth muscle cells, and endothelial progenitor cells [105]. PGI2 is rapidly converted to 6-keto PGF1α [104]. In regard to cardiovascular homeostasis, PGI2 is a potent vasodilator, an inhibitor of platelet aggregation, leukocyte adhesion, and VSMC proliferation [104]. PGF2α is widely distributed and has been shown to be present in multiple species including mice, cows [106], guinea pigs [107], and humans [108]. It plays a large role in the female reproductive system (e.g. ovulation, parturition) [109], arthritis [110], renal function [111], arterial contraction [112], brain injury [113], pain [114], and myocardial dysfunction [115]. PRO-RESOLUTION LIPID MEDIATORS Lipoxins are produced by a sequential process that begins with lipoxygenases acting on arachidonic acid and then continues through other enzymes [2]. They act on a variety of cells, including neutrophils, eosinophils, monocytes, macrophages, T cells, dendritic cells, and fibroblasts [2]. One of the main roles of lipoxins is to inhibit neutrophil infiltration into inflamed areas [2], though they also block the secretion of TNF from T cells [2]. Additionally, lipoxins will increase the rate of phagocytosis as well as increase IL-10 production [116]. Lipoxins have been detected in a variety of disease states, including periodontis [2], peritonitis [117], colitis [118], asthma [119], cystic fibrosis [120], and ischaemia-reperfusion injury [121]. Resolvins are another category of pro-resolution lipid mediators which were first identified in 2000 [2]. There are two categories of resolvins, the E-series and the D-series, which are derived from EPA and DHA, respectively [2]. The E-series resolvins, RvE1 and RvE2, target mucosal epithelial cells, neutrophils, macrophages, dendritic cells, and T-cells [116] and have a wide variety of

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functions. For example, they reduce neutrophil infiltration [2], inhibit NF-kB reporter gene activation, and reduce dendritic cell IL-12 production [116]. Additionally, they will increase PMN apoptosis, lipoxin production, and microbial killing [116]. The D-series resolvins are particularly interesting in that the brain, synapses, and retina are highly enriched in DHA and therefore will produce this series of resolvins more readily [2]. There are four members of this group, RvD1, RvD2, RvD3, and RvD4 [2]. RvD1 appears to be the most studied member of this group, with RvD2 having the next most known information. RvD1 and RvD2 both act on neutrophils, macrophages, and endothelial cells [116]. RvD1 has a role in ending neutrophil recruitment [2], protecting kidneys from ischaemia-reperfusion injury [122], and regulating macrophage function [122]. Additionally, RvD1 will increase the rate of phagocytosis and IL-10 expression [116]. RvD2 has similar roles, but it will also increase nitric oxide and prostacyclin production in endothelial cells as well as microbial killing and clearance [116]. A third category of pro-resolution lipid mediators is the protectins. These lipid mediators are produced from DHA, and the most studied is protectin D1. Protectin D1 (PD1) is produced by leukocytes and human peripheral blood mononuclear cells [2], and it targets neutrophils, macrophages, T-cells, microglial cells, and epithelial cells. As with other pro-resolution lipid mediators, protectin D1 has many functions, including blocking T-cell migration [123], decreasing TNF and interferon-gamma secretion [123], down regulating NF-κB and COX-2 expression [116], as well as upregulating neuroprotective actions [116] and CCR5 expression on T-cells [116]. Serhan et al. have found that PD1 essentially shortens the resolution interval of infection [2]. This occurs via a similar mechanism to RvE1, as these two lipid mediators reduce the influx of neutrophils as well as increase neutrophil phagocytosis by macrophages [2]. A final group of pro-resolution lipid mediators is the maresins, with maresin 1 (MaR1), being the main lipid mediator of the group. MaR1 is derived from DHA and is produced by macrophages [116]. Similarly to the other pro-resolution lipid mediators, MaR1 inhibits neutrophil infiltration and enhances neutrophil phagocytosis by macrophages [116]. It has been shown to be protective in murine peritonitis as well as both the DSS and TNBS models of colitis [116, 124].

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As previously mentioned, many prostaglandins have been shown to have both pro-inflammatory and pro-resolution effects. PGE2 has been shown to have antiinflammatory effects on neutrophils, monocytes, and natural killer cells [104] and has been demonstrated to suppress Th1 differentiation, B cell functions, and allergic reactions [104]. PGI2 also can have anti-inflammatory effect on immune responses, particularly in regard to asthma and allergy. In allergy, some studies have demonstrated that PGI2 and its receptor play a role in Th2-mediated responses [104]. In this system, signaling through the receptor likely enhances the production of IL-10, an antiinflammatory cytokine, by Th2 cells. BIOSYNTHEIS OF CYTOKINES AND CHEMOKINES Cytokines are proteins which serve as chemical messengers with cells of the immune system utilize to modulate inflammation [125, 126]. These proteins also can be involved in T cell differentiation, migration, and polarization into subtypes [127]. Cytokines play roles in both acute and chronic inflammation and can be classified based on either nature of immune response or upon cell type and location [125]. Cytokines are typically not stored, rather they are produced as needed by various lymphocytes. Typically their secretion is limited [128] and various signals can cause these proteins to be produced. Some cytokines are produced as a precursor protein (e.g. IL-1β, IL-18, TNF-α) that must be processed by a protease such as caspase-1 [129], or for TNF-α, TNF-α-converting enzyme (TACE/ADAM17) [130]. Others do not need to be processed to be active (e.g. IL1α and IL-33) [131]. Chemokines are small proteins (approximately 8-14 kDa) which are involved in the immune response, particularly in regards to the trafficking of leukocytes [127, 132]. Over 50 different chemokines have been identified in vertebrates. All chemokines are structurally related as they share conserved sequences, including four conserved cysteines [127]. The chemokines are classified into four categories, based upon the configuration of these cysteines [133]. Chemokines function via activation of various G-protein coupled receptors [134] which are expressed in a wide variety of cells, including neurons, glial cells, T-cells, and

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various leukocytes [135]. Together these proteins regulate both the proinflammatory stage of inflammation as well as participate in the resolution of inflammation. PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES As with lipid mediators, cytokines and chemokines can either be proinflammatory or pro-resolution/anti-inflammatory. The main cytokines which are pro-inflammatory are members of the IL-1 family, IL-6 family, and TNF family [125, 136]. The main chemokine which is pro-inflammatory is CCL2. The IL-1 family contains multiple pro-inflammatory cytokines, including IL-1α, IL-1β, IL-18, and IL-33. IL-1α is expressed in a variety of cells, including keratinocytes and endothelial cells whereas IL-1β is mainly produced by monocytes and macrophages [137]. Regarding location of action, IL-1α typically signals locally as it is usually associated with the plasma membrane whereas IL1β circulates systemically [137]. As IL-1 is expressed in large amounts in the skin, it is implicated in various skin diseases such as psoriasis and contact hypersensitivity [137]. IL-1 is also involved in asthma, Crohn’s disease, and ulcerative colitis [137]. IL-18 is expressed by macrophages, dendritic cells, and epithelial cells [137]. IL-33 is abundantly expressed in many tissues [137]. Neutrophils, monocytes, and macrophages will respond to IL-1, IL-18, and IL-33 [137]. Elevated levels of both IL-18 and IL-33 have been found in patients with rheumatoid arthritis [137]. IL-6 is produced by a variety of immune cells including macrophages, dendritic cells, mast cells, and B cells [138]. Interestingly, IL-6 is also produced by nonimmune cells including endothelial cells, fibroblasts, and epithelial cells [138]. Levels of IL-6 are elevated in some autoimmune inflammatory diseases including rheumatoid arthritis and Crohn’s disease [139] and asthma [140]. IL-6 has also been shown to be involved in the modulation of TH1 and TH2 cells [138] and works with TGFβ to promote differentiation of TH17 cells [138]. It also has the ability to regulate expression of different chemokines, such as CXCL1 and CXCL5 [138]. TNF, a major pro-inflammatory cytokine, was first identified in 1975 and human

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TNF was cloned in 1985 [141]. It is produced by a wide range of cells, including macrophages, T and B lymphocytes, mast cells, neutrophils, endothelial cells, and natural killer cells [141]. TNF is initially produced as pro-TNF, which must be cleaved in the extracellular domain by TNF-α converting enzyme (TACE, also known as ADAM17), to release the soluble form of TNF [141]. Production of TNF and the detection of it by cells can produce a wide variety of proinflammatory functions. For example, endothelial cells will not only release chemokines and recruit leukocytes, but they will also increase COX-2 expression which can increase PGI2 expression and therefore promote vasodilation [141]. TNF can also induce the expression of pro-coagulant proteins and increase vascular permeability [141]. IL-12 and IL-23 are pro-inflammatory cytokines from the IL-12 cytokine family. They are both produced by dendritic cells and macrophages in response to microbial pathogens, and IL-12 is also produced by B cells [142]. IL-12 induces production of IFN-γ by both T cells and natural killer cells and is also involved in TH1 differentiation [142]. Differing from IL-12, IL-23 plays a role in TH17 development by stabilizing IL-17 expression and including the pathogenic phenotype in TH17 cells [142]. CCL2 (MCP-1 in humans) is a pro-inflammatory chemokine that is expressed in monocytes, macrophages, fibroblasts, endothelial cells, and mast cells [133]. As such, an elevated level of CCL2 is observed in many chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atherosclerosis, and asthma [133]. CCR2 is the receptor for this chemokines and is expressed on monocytes, activated T cells, natural killer cells, and dendritic cells [133]. A major function of CCL2 is to produce a gradient that directs the movement of leukocytes into inflammatory sites and tissue injury sites [133]. PRO-RESOLUTION CYTOKINES AND CHEMOKINES The subset of cytokines and chemokines which are pro-resolution include mainly the IL-10 family and the IL-12 family of cytokines [125]. IL-10 was first described as a T helper 2 specific cytokine [143], and almost all

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cells of the immune system can express IL-10 – including dendritic cells, macrophages, natural killer cells, eosinophils, neutrophils, mast cells, B cells, and T cells [144]. IL-10 is important in protecting the body from infection-associated issues such as autoimmunity, allergy, and immunopathology [144]. It also has the capability to inhibit activated macrophage functions including synthesis of monokines and nitric oxide as well as expression of IL-12 and class II MHC [144]. Two members of the IL-12 family function as inhibitory cytokines – IL-27 and IL-35. IL-27 is typically produced by antigen-presenting cells while IL-35 is produced by Treg cells [142]. IL-27 can work with IL-12 and/or IL-2 to induce IFN-γ production by both T cells and natural killer cells [142]. However, IL-27 can also inhibit IL-2 production which inhibits the development of TH17 cells as IL-2 is required for TH17 proliferation [142]. Additionally, IL-27 is able to induce IL-10 production, which will also repress development of TH17 cells [142]. IL-35 will also suppress T cell proliferation [142]. CONCLUSION Inflammation is a complex process that is a critical component of multiple disease states. A variety of biochemical mediators (e.g. eicosanoids, cytokines) play distinct roles in the regulation of the inflammatory process – ranging from initiation of inflammation to the resolution of inflammation. As such, the production and inhibition of these mediators has been examined as potential drug targets for controlling inflammation. Interestingly, as more studies are conducted, this field continues to evolve, expand, and become more complex. With each new study, we gain more insight into the mediators of inflammation and how we may be able to utilize them to improve inflammatory conditions. CONFLICT OF INTEREST The authors confirm that authors have no conflict of interest to declare for this publication. ACKNOWLEDGEMENTS This work was supported by research grants from the Veteran’s Administration

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(VA Merit Review I BX001792 to CEC and a RCS award 1 3F-RCS-002to CEC) and from the National Institutes of Health (HL125353 to CEC). The contents of this chapter do not represent the views of the Department of Veterans Affairs or the US Government. REFERENCES [1]

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[135] Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov 2014; 13(7): 533-48. [http://dx.doi.org/10.1038/nrd4334] [PMID: 24948120] [136] Striz I, Brabcova E, Kolesar L, Sekerkova A. Cytokine networking of innate immunity cells: a potential target of therapy. Clin Sci 2014; 126(9): 593-612. [http://dx.doi.org/10.1042/CS20130497] [PMID: 24450743] [137] Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol 2010; 10(2): 89-102. [http://dx.doi.org/10.1038/nri2691] [PMID: 20081871] [138] Rincon M. Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol 2012; 33(11): 571-7. [http://dx.doi.org/10.1016/j.it.2012.07.003] [PMID: 22883707] [139] Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988; 31(6): 784-8. [http://dx.doi.org/10.1002/art.1780310614] [PMID: 3260102] [140] Neveu WA, Allard JL, Raymond DM, et al. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respir Res 2010; 11: 28. [http://dx.doi.org/10.1186/1465-9921-11-28] [PMID: 20205953] [141] Bradley JR. TNF-mediated inflammatory disease. J Pathol 2008; 214(2): 149-60. [http://dx.doi.org/10.1002/path.2287] [PMID: 18161752] [142] Vignali DA, Kuchroo VK. IL-12 family cytokines: immunological playmakers. Nat Immunol 2012; 13(8): 722-8. [http://dx.doi.org/10.1038/ni.2366] [PMID: 22814351] [143] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170(6): 2081-95. [http://dx.doi.org/10.1084/jem.170.6.2081] [PMID: 2531194] [144] Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC. Regulation of adaptive immunity; the role of interleukin-10. Front Immunol 2013; 4: 129. [http://dx.doi.org/10.3389/fimmu.2013.00129] [PMID: 23755052]

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CHAPTER 4

Wound Healing and Dermatologic Aspects of Inflammation Lisa J. Gould, Mary Elizabeth Hanley* Wound Recovery & Hyperbaric Medicine Center, Kent Hospital, Warwick, Rhode Island, USA Abstract: The skin is a highly complex organ that provides a wide variety of functions, including protection against toxins, pathogenic organisms and physical insults. When there is a breach in this very important barrier, it becomes clear that the skin is also an immune organ. There is a yin and a yang to the role of inflammation in wound healing. Although most of us take it for granted, normal wound healing requires a rapid inflammatory response with quick resolution. When this basic process is disrupted, either due to systemic illness or local factors, pathologic abnormalities in wound healing occur. This chapter will examine the normal inflammatory response as well as the factors that lead to chronic non-healing wounds. Identification of abnormal cellular and molecular immune responses may lead to targeted therapeutic strategies that promote harmony in the wound healing symphony.

Keywords: Aging, Diabetes, Inflammation, Lymphocytes, Macrophage, Neutrophils, Psoriasis pyoderma gangrenosum, Tumor necrosis factor, Venous insufficiency. INTRODUCTION Inflammation and the inflammatory process play key roles both in normal and abnormal wound healing. The absence or inability of a host to mount an inflammatory response will cause a wound to cease to progress through the final stages of healing and lead to development of what is referred to as a “nonhealing” Address correspondence to Mary Elizabeth Hanley: Wound Recovery & Hyperbaric Medicine Center; Kent Hospital; 455 TollGate Road; Warwick, Rhode Island 02886, USA; Tel: 401-736-4646; Fax: 401-736-4248; Email: [email protected] *

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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or “problem” wound. Numerous studies in murine models have shown that a lack of pro-inflammatory cells will cause impaired healing in surgical wounds [1 - 3]. The Macrophage has earned the title of “Conductor” of the wound healing symphony for its pivotal role in overseeing the initiation of the inflammatory phase, maintaining the population of phagocytizing cells for debridement and removal of bacteria and for regulating the transition to the non-inflammatory proliferative phase of wound healing. Despite the fact that inflammatory mediators and the inflammatory process are integral to wound healing, there are pathological conditions in which the inflammation and or its mediators run amok and can cause serious, sometimes permanent, dermatological injury and scarring. These situations can arise when patients have a co-existing autoimmune or rheumatological disorder, or sometimes are idiopathic in nature. The skin is the largest organ in the mammalian body. It is made up of essentially 2 separate layers separated by a basement membrane. Because the skin is such a large organ system it makes sense that a veritable plethora of disorders (some inflammation driven, others not) will manifest themselves in the dermal structures. Most chronic wounds are ulcers that are associated with ischemia, diabetes mellitus, venous stasis disease or pressure. However, reactive cutaneous disorders such as erythema nodosum, pyoderma gangrenosum, Cutaneous polyarteritis nodosa, and Sweet’s Syndrome are examples of the inflammatory process in wound healing gone awry, either due to lack of inflammatory mediators, or to an overproduction of such. Many of these cutaneous manifestations are associated with systemic inflammatory conditions such as Ulcerative colitis and Crohn’s disease and will respond to local or systemic steroids or immunosuppressant therapy aimed at moderating the inflammatory process. In this chapter we examine the inflammatory response that promotes skin wound healing with an emphasis on identifying potential therapeutic targets when inflammation is either deficient, excessive or poorly timed. NORMAL DERMATOLOGICAL RESPONSE IN WOUND HEALING Wound healing is a complex process involving interactions with the extracellular

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matrix, soluble mediators, resident cells of the skin and transient inflammatory cells. The main goal of this process is to reestablish homeostasis and achieve tissue integrity. Most authors agree on four overlapping phases to wound healing: 1. 2. 3. 4.

Hemostatic Inflammatory Proliferative Remodeling

These occur in most healthy persons in a timely and logical progression. A lack of, or excess of any one mediator may prolong or prevent the stepwise progression the wound needs to progress through in order to fully heal. Hemostasis occurs immediately after injury and is characterized by vasoconstriction and fibrin clot formation. Platelets not only activate the clotting cascade, they also secrete pro-inflammatory growth factors such as transforming growth factor (TGF)-β, platelet derived growth factor (PDGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) and cytokines which initiate healing [4]. The Inflammatory Phase of Wound Healing In addition to establishing control of hemorrhage, the hemostatic phase initiates the signals to re-establish homeostasis. Simultaneous with platelet aggregation, the resident cells (keratinocytes, fibroblasts, endothelial, Langerhans) secrete mediators to recruit leukocytes and skew the process towards rapid wound closure. The inflammatory phase is characterized by the sequential infiltration of neutrophils, macrophages and lymphocytes [5]. Neutrophils Neutrophils are the first immune cells to reach the injured tissue. Takamiya et al. observed that neutrophils begin to accumulate in dermal wounds after 2 hours, reaching a peak after 33-49 hours [6]. In this early phase the soluble mediators most prevalent at the wound site are: IL-10, GM-CSF, IFN-γ and TNF-α, while

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the early cell infiltrate is composed predominantly of neutrophils [6, 7]. Neutrophil functions include: (a) phagocytosis of infectious agents with release of ROS, cationic peptides, eicosanoids and proteases; (b) amplification of the inflammatory response through secretion of mediators such as TNF-α, IL-1β and IL-6; (c) macrophage activation through phagocytosis; (d) stimulation of the repair response by secreting VEGF and IL-8 [8]. In the absence of infection, neutrophil proliferation will cease the first few days after injury. This signifies the end of the early inflammatory phase of wound healing. Monocytes and Macrophages Monocytes are also attracted to the wound by chemotactic factors released from the platelets. Monocytes behave similarly to neutrophils in that they respond to chemical attractants, phagocytize and release various enzymes. However, monocytes also have the additional capacity to mature into macrophages. First named by Elie Metchnikoff for their tremendous phagocytic ability, the early wound macrophages are a major defense system against invasion by bacteria, viruses, fungi and protozoa [9]. Migrating into the wound 48 to 96 hours after the initial injury, macrophages become the predominant cell population at this midstage of the inflammatory process. Although known for their hearty appetite, macrophages exhibit a spectrum of phenotypic characteristics ranging from the classically activated inflammatory phenotype (M1) to the alternatively activated or anti-inflammatory phenotype (M2). Studies of macrophages isolated from wounds suggest that these distinct phenotypes may not apply to macrophages in the wound bed. There is certainly a temporal profile in which wound bed macrophages move from pro-inflammatory to anti-inflammatory cytokine production, however, this appears to be due to macrophage plasticity rather than distinct populations of macrophages that move in and out of the wound bed. In fact, the wound macrophage is probably best thought of as a hybrid with both M1 and M2 characteristics that senses and responds to the wound environment [10]. Thus, both resident and recruited pro-inflammatory macrophages amplify inflammation via an autocrine loop driven by TNF-α until the tissue damage or infection is controlled. Like the neutrophils, macrophages carry out their antimicrobial function via phagocytosis, generating highly reactive radicals such as nitric oxide, superoxide anion and peroxide. Secretion of inflammatory

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cytokines (TNF-α, IL-1β, IL-6, and IL-12) draws additional cells to the site of injury [11]. Following damage control, macrophages begin phagocytosis of apoptotic cells, including apoptotic neutrophils. This accomplishes two things: 1) ingestion of the neutrophils prevents lytic release of their noxious contents into the wound bed, thus reducing further inflammatory stimulation and tissue destruction and 2) ingestion of the apoptotic neutrophils triggers the production of anti-inflammatory cytokines by the macrophage, thus inducing the transition to the anti-inflammatory, reparative macrophage phenotype [12, 13]. In addition to spontaneous neutrophil apoptosis, macrophage contact with neutrophils induces apoptosis, promoting resolution of the inflammatory phase [11]. This is just one example of how the macrophage regulates the wound healing process. The reparative macrophage phenotype is characterized by secretion of cytokines that reduce inflammation (IL-10) and growth factors that promote formation of the provisional matrix and angiogenesis (TGF-1β, VEGF, and PDGF) [11]. At this stage, macrophages contribute to fibroblast recruitment and differentiation of the myofibroblast, leading to collagen deposition and wound contraction. Macrophage matrix metalloproteinase (MMP) production allows endothelial cells to migrate into the wound where they can respond to VEGF secreted by macrophages and by keratinocytes at the wound edge [14]. In a non-inflammatory role, macrophages have recently been shown to be critical for guiding the endothelial sprouts to fuse, promoting vascular anastomoses [15]. Classical studies in which guinea pigs were treated systemically with antimacrophage serum and steroids to fully deplete circulating monocytes demonstrated the critical role of the macrophage for wound debridement and fibroplasia [16]. Exogenous supplementation of macrophages via intradermal injection into rat cutaneous wounds has been shown to increase collagen synthesis and wound breaking strength [17]. Recent reports using transgenic mouse models have confirmed and delineated the essential role of the macrophage throughout the adult healing process [18 - 20]. Specifically, using selective depletion of macrophages in the transgenic mouse skin wounds, Lucas et al. demonstrated that macrophage depletion during the early stage of repair attenuates epithelization, granulation tissue formation and wound contraction while depletion during the reparative phase results in severe hemorrhage, fibrin exudate and detachment of

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the epidermal wound edge [19]. Because they sense and adapt to their surroundings, macrophages play a critical role in orchestrating the wound healing process. Thus, while neutrophils are the first line of defense, the macrophages are the conductors in this highly orchestrated symphony, as they oversee and regulate the performance of other cellular and inflammatory components [21]. Lest we give macrophages all the credit, we would be remiss not to consider the important role lymphocytes play in wound healing as well. This role was reviewed extensively by Schaffer and Barbul and demonstrated that the role of lymphocytes in healing is related to their ability to produce cytokines and growth factors known as lymphokines [22]. It is also known that lymphocytes exert a regulatory effect on fibroblast activity and wound fibroplasia as well. Lymphokines have been shown to regulate endothelial cell functions and to induce angiogenesis in vivo [23]. T lymphocytes In human wounds, T lymphocytes increase progressively with time and peak between 8 and 14 days post wounding, corresponding to the late proliferative/ early remodeling phase. The exact role of T lymphocytes in wound healing is not completely understood although delayed or decreased T-cell migration is associated with impaired wound healing. In 1991 Reusch hypothesized that T lymphocytes play an important role in the regulation of epidermal regeneration, and that wounding of the epidermis may stimulate the release of T cell chemotactic factors by the injured epithelial cells themselves [24]. Subsequent studies confirmed a reciprocal relationship between keratinocytes and epidermal T cells in which both cell types become activated and produce inflammatory cytokines [25]. Some studies report the CD4+ cells (T-helper cells) have a beneficial role in wound healing and that CD8+ cells (T suppressor-cytotoxic cells) play an inhibitory role in wound healing [26]. Interestingly, both subtypes can be found in wounds up to 7 or 8 months post wounding, albeit in much smaller numbers. T-helper cells are now implicated in several of the chronic immune disorders that affect wound healing. Specifically, dysregulation of T helper mediated inflammation is involved in the pathogenesis of psoriasis and hidradenitis suppurativa, resulting in elevated IL-17A and IL-23 [27]. CD3+ T-

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lymphocytes are another subset of T lymphocytes that infiltrate the newly forming epidermis in wounds and embed themselves into the newly forming epithelium. Actively hypertrophic burn scars are infiltrated with an abundance of CD3+ cells with persistently high levels of IFN-γ compared to scars in remission or normotrophic scars [28, 29]. However, work done in 1999 by Agaiby and Dyson showed that even in normally healing wounds, CD3+ lymphocytes are present in the epithelium and that the T cell/keratinocyte interaction may be of biological significance [30]. Mice that are genetically deficient in both T- and B-cells form poor quality scar tissue that has less tensile strength [31]. Skin gamma-delta Tcells, also called dendritic epidermal T-cells (DETC) are a subset of CD3+ cells that regulate many aspects of wound healing. These cells are responsible for maintaining tissue integrity, defending against pathogens and regulating inflammation. DETC are activated by stressed, damaged or transformed keratinocytes and produce fibroblast growth factor 7 (FGF-7) and insulin-like growth factor-1, to support keratinocyte formation, proliferation and cell survival. It is theorized that cross talk between skin gamma-delta T-cells and keratinocytes contributes to the maintenance of normal skin and wound healing. Mice that are lacking or defective in skin gamma-delta T-cells show a delay in wound closure and a decrease in the proliferation of keratinocytes at the wound site [32, 33]. The Proliferative Phase The proliferative phase follows the inflammatory phase with some overlap. During the proliferative phase the epithelium proliferates and migrates across the provisional matrix within the wound. The most prominent cell types in the proliferative phase are fibroblasts and endothelial cells. These function to support capillary growth, collagen formation and ultimately the formation of granulation tissue at the site of the wound. Fibroblasts produce collagen, glycosaminoglycans and proteoglycans that form the extracellular matrix (ECM). As discussed above, macrophage production of anti-inflammatory mediators and modulation of angiogenesis is critical during this phase. The Remodeling or Maturation Phase The remodeling or maturation phase begins after about 3 weeks and can go on to

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last for years after the initial injury occurred. It is during this phase that collagen is deposited and degraded in an equilibrium producing fashion. This equilibrium results in a constant amount of collagen being present in the wound. Collagen deposition peaks by about the third week post wounding. At the same time that collagen production is peaking, the wound is beginning to undergo contraction. Contraction is an ongoing process in a wound that results from the activity of specialized fibroblasts called myofibroblasts. The myofibroblasts actually resemble contractile smooth muscle cells. Granulation tissue contains mostly myofibroblasts. Normal scar contains only fibroblasts. In the development of a normal scar, myofibroblasts either undergo apoptosis, or they revert back to fibroblasts [34]. It becomes fairly obvious that for any wound to heal in a timely fashion, inflammation in the dermal structure must be kept to a minimum. This can be accomplished by minimizing tissue destruction, clearing the wound of cellular debris, and maintaining a moist wound environment. Although elimination of macrophages at this stage of repair in sterile wounds does not result in any demonstrable deficit in wound healing, they are still present in the maturing scar [19]. Persistence of reactive suture material in the wound bed incites a foreign body reaction with mobilization of macrophages, production of TNF-α and IL-6 and the possibility of wound complications, hypertrophic scar or keloids [35]. Interventions that minimize the amount of reactive suture material used to close a wound are helpful in minimizing the dermal inflammatory response and speed the healing process [35, 36]. Recent studies have shown that in the fetal model, scarless wound repair is possible due, in part, to an immature inflammatory response to surgical wounding. Thus one way to minimize scarring is to eliminate or at least reduce inflammation [37, 38]. WHY DON’T CHRONIC WOUNDS HEAL? Although chronic wounds are rarely seen in individuals who are otherwise healthy, in the United States they affect 6.5 million patients [39]. It is no surprise that chronic wound patients also suffer from multiple other illnesses, particularly diabetes and obesity and that the problem of chronic wounds is rapidly growing as our population ages. It is theorized that chronic or “recalcitrant “ wounds, such as diabetic foot ulcers, become “stuck” in the inflammatory phase of wound healing and fail to progress toward the proliferative and remodeling phases. Although it is

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still not clear exactly what makes a wound become chronic, there are a number of ‘host’ and ‘local’ factors that have been implicated as contributing to the process. Hyperglycemia in and of itself has deleterious effects on wound healing. Chronic hyperglycemia leads to the production of advanced glycation end products (AGE’s) that induce the production of inflammatory molecules (TNF-α, and IL-1) which interfere with collagen synthesis [40]. The immune function in diabetic patients is altered such that they demonstrate decreased chemotaxis, ineffective phagocytosis, and poor bacteria killing and reduced expression of heat shock proteins [4, 41]. Reduced bioavailability of cytokines and growth factors is implicated in the pathogenesis of chronic wounds [42, 43]. In order for normal wound healing to proceed, there must be a balance between the accumulation of collagenous and noncollagenous extracellular matrix components. While MMPs play a pivotal role in wound debridement and in angiogenesis, epithelialization, and remodeling of scar tissue, the ratio of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is critical for growth factor bioavailability and for balancing matrix deposition and degradation [44]. Several research studies have found elevated MMPs and decreased TIMPs in chronic wounds [45 - 47]. There is also a growing body of evidence that resident cells in chronic wounds undergo phenotypic changes that impair their capacity for proliferation and movement. An example of this is the fact that fibroblasts isolated from pressure and venous ulcers have a decreased ability to proliferate, and this loss of proliferative ability is directly correlated with the wound failing to heal [48]. Tumor necrosis factor-α was cloned almost 30 years ago. Since then, a “super family” of tumor necrosis factors (TNFs) and their receptors have been identified. TNF-α signals through two membrane receptors, TNFR1 and TNFR2 and regulates a number of critical cell functions including cell proliferation, survival, differentiation and apoptosis [49]. TNF-α is a powerful pro-inflammatory agent that controls many macrophage functions. TNF-α has been found in large quantities after traumatic injury to tissue or after exposure to bacterial lipopolysaccharide (LPS). It is one of the most potent and prevalent mediators of

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the inflammatory response. TNF-α controls the production of a pro-inflammatory cytokine cascade early in the course of trauma or bacterial invasion. It also stimulates production of prostaglandins and platelet activating factor [50]. Macrophage-derived TNF-α is now implicated in juvenile and adult rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, ankylosing spondylitis, atherosclerosis, and sepsis [49, 51]. TNF-α is considered to be the key inflammatory cytokine in rheumatoid arthritis [52]. It is found in high levels in patients with the disease and theorized to be responsible for the chronic synovitis seen in patients with this disease. This pro-inflammatory cytokine is also now implicated in fibroproliferative disorders such as Dupuytren’s, therefore may be an important therapeutic target [53]. Patients with many of these inflammatory disorders also present with chronic, non-healing wounds, thus TNF-α is also being investigated as a therapeutic target for modulating wound repair [54]. However, demonstrating the incredible complexity of the inflammatory pathways involved in wound healing and the importance of macrophages for modulating that response, studies have shown macrophage derived TNF-α is also a critical antiinflammatory mediator required for termination of the fibrotic reaction [55]. This is just one more illustration of the complex autocrine, paracrine and intercellular signaling that makes single factor modulation of wound healing an elusive goal. COMMON WOUND HEALING PROBLEMS AND INFLAMMATION Diabetes Diabetes mellitus is characterized by a number of dermatologic diseases, including a high rate of fungal and bacterial cutaneous infections, xerosis and inflammatory dermatologic disorders. These disorders are most frequent in patients with HgbA1c>8mmol/mL and diabetes duration >5 years, suggesting that both hyperglycemia and chronic inflammation contribute to the global deficit in wound healing associated with diabetes [56]. The most frequently cited impairment in diabetic healing is the diabetic foot ulcer (DFU). Although less common than the other dermatologic diseases, DFUs impose a huge burden on the medical system and the affected patients, substantially increasing the morbidity and mortality of diabetes [57]. DFUs result from a critical triad of minor or repetitive trauma, foot deformity and neuropathy. Although they begin as acute

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wounds that may appear relatively minor, they commonly progress to chronic non-healing wounds with a high risk of infection and amputation [58]. There is substantial evidence to support a causative role for inflammation in the pathogenesis of diabetes, both systemically and in insulin-sensitive tissue, including skin [59, 60]. Initially characterized by decreased early inflammatory infiltration, diabetic wounds subsequently have increased numbers of neutrophils and macrophages with increased pro-inflammatory and reduced anti-inflammatory cytokines, as well as prolonged expression of the chemokines CXCL2 and CCL2 [58, 61]. Macrophage function, including phagocytosis and efferocytosis is impaired, inhibiting the transition to the reparative stage and leading to excess tissue destruction [62]. Martins et al. demonstrated elevated MMP 1, 2, 8 and 9, with decreased TIMP 1 and 2 in diabetic wound tissue [63]. The abnormally elevated MMP/TIMP ratio impairs cell migration, prolongs inflammation, reduces the bioavailability of active cytokines and growth factors and leads to net destruction of the tissue matrix [60]. Chronic hyperglycemia leads to the production of advanced glycation end products (AGEs) which have been shown to activate NADPH oxidase and increase reactive oxygen species, further enhancing the production of inflammatory cytokines and up-regulating production of MMPs [64]. Finally, endothelial progenitor cells (EPCs) have been shown to be decreased in patients with DFU and in those at risk for DFUs. Consistent with the other cellular and signaling abnormalities associated with diabetes, defects in both EPC function and recruitment appear to be related to chronic inflammation and hyperglycemia [65, 66]. Thus, the majority of wound healing defects in diabetes can be attributed to a heightened inflammatory state. Although most of the research findings are based on hyperglycemic mouse models, it has been shown that there is increased inflammation in human diabetic skin and blood vessels that leads to impaired wound healing and that these abnormalities are consistent with those found in the diabetic animal models [67]. Venous Insufficiency Venous leg ulcers occur in a small but significant number of people with impaired venous drainage either due to valvular incompetence or venous outflow obstruction. Hemosiderin deposits are a diagnostic characteristic of venous insufficiency, yet it is only recently that iron has been implicated as playing a

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pivotal role in inducing and maintaining inflammation that impedes healing. Under conditions of venous hypertension and stasis, erythrocytes extravasate into the subcutaneous tissue. Recognized as foreign, they are engulfed by macrophages. Subsequent release of hemoglobin bound iron into the interstitium results in the characteristic hemosiderin staining and leads to a series of untoward effects including induction of MMP hyper activation with over-expression of MMP9 and activation of pro-inflammatory M1-like macrophages [68 - 70]. A certain percentage of patients are at increased risk of ulceration due to genetic mutations that alter iron metabolism and increase iron release from the macrophages [68, 71]. There is now good evidence that iron overload results in persistent, unrestrained activation of M1-like macrophages [11, 72]. The release of high levels of TNF-α creates a vicious cycle in which more macrophages are attracted to the site and continuously activated. Free radicals released from the macrophages induce oxidative damage, cause premature senescence of the resident wound fibroblasts, and impair normal signaling (Fig. 1).

Epldermis

Mechanisms of Chronic Poor Healing Tissue Breakdown & Fibrosis in CVD Venous Hypertension

Dermis

Haemosiderin Deposition

TNF-a ROS

Erythrocytes With lion ? Genetic Inebility to Counter Iron Overtoad

Iron Icaded Macrophages by Er/throphagocytosis

Iron-dependent activation of M1 Macrophages

MMP Activation Fibrobtast Senescence IL-6 (constantiy secreted in VLU)

? Hepcidin ? Ferroportin Speciflc Roies Uncertain

Fig. (1). Pathogenesis of venous ulcers. Under conditions of venous hypertension erythrocytes extravasate into the insterstitium. Macrophages become iron loaded resulting in persistent iron-dependent activation with production of high levels of TNF-α and reactive oxygen species. Iron dependent activation of matrix metalloproteinases results in tissue destruction. Venous ulcer disease has a strong genetic component that contributes to the iron overload. (Reprinted under CC BY license, Wright et al. 2014 [101]).

Experimental studies in a mouse model of iron overload have demonstrated that

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iron chelation prevents generation of the proinflammatory M1 macrophage population and prevents impaired wound healing [72]. Thus, potential therapeutic strategies aimed at reducing the macrophage activation (iron chelation) and moderating the by-products of activated macrophages with TNF-α inhibitors and free radical scavengers may improve healing and resolve the excessive inflammatory response so characteristic of venous leg ulcers. Aging and Wound Repair Although fundamental questions remain about the mechanisms that contribute to the impact of aging on wound healing, it is well established that the elderly account for a disproportionate share of all patients affected by chronic and infected wounds. The mechanisms for delayed wound repair with aging are multifactorial, including that older adults have multiple co-morbidities and take multiple medications that impact wound healing. However, there is also clear evidence for a direct impact of age alone on wound healing [73]. Among the potential explanations for impaired healing is the condition of ‘inflammaging’, defined as the continuous low-grade inflammation associated with aging. This chronic, but asymptomatic, inflammatory state is characterized by increased systemic levels of IL-6, IL-1β and TNF-α [74]. Despite (or because of) increased circulating pro-inflammatory mediators, the response to systemic insults is blunted at multiple levels, rendering elderly individuals more susceptible to infections and contributing to an increased incidence of chronic disease and autoimmune conditions. Normally the skin immune system provides protection from infection and surveillance for cancers, damaged cells and autoimmune reactions. With intrinsic aging or UV-induced photoaging, that protection is altered. Chronic inflammation results in accumulation of ROS and MMPs, followed by cell loss, thinning of the epidermis and flattening of the dermal-epidermal junction. There is decreased responsiveness of the endogenous antioxidant enzyme system to stress, the complement system is over activated and the macrophages overburdened [74 - 77]. The net result is tissue destruction and matrix degradation, i.e., impaired wound healing. Age-associated defects have been shown in murine models at all stages of the immune response to wounding, including impaired neutrophil recruitment,

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impaired phagocytosis, delayed but prolonged recruitment of macrophages to the wound bed and enhanced TNF-α expression by resident macrophages [17, 26, 78 80]. To understand the clinical relevance, these defects will need to be verified in human wounds and then shown to be responsive the therapeutic modulation. Psoriasis is a prototypical T-cell mediated inflammatory skin disorder associated with the development of an inflammatory arthritis. It is characterized by expansion of Th1 and Th17 T cells with elevated expression of inflammatory cytokines, e.g. TNF-α, IL-1, and IL-6, in the skin and blood (Fig. 2). IL-17 induces autocrine IL-22 production resulting in inflammation and thickening of the epidermis, however, it is TNF-α that appears to be the key driver of the inflammatory disease process [81, 82]. Individuals with active skin disease have elevated levels of TNF-α in the skin lesions and blood and there is an association with other TNF-α driven inflammatory diseases, including ulcerative colitis, Crohn’s disease, lymphoma, diabetes, obesity and hypertension [81, 82]. Medications such as etanercept and infliximab, targeted at inhibiting TNF-α are now routinely used in treating these diseases. The anti TNF-α medications have been on the market in the United States since 1998, and work by affecting signaling pathways which lead to cell cycle arrest, apoptosis and suppression of cytokine production [83]. Treatment with TNF-α blockers reduces the number of infiltrating synovial granulocytes and macrophages, as well as decreasing the expression of chemokines IL-8 and monocyte chemotactic protein [84]. In addition to suppressing the psoriatic symptoms, TNF antagonists may play a role in modulating the metabolic diseases associated with psoriasis, thereby decreasing cardiovascular risk. Interestingly, despite the chronic inflammatory state and elevation of TNF-α both systemically and in psoriatic skin, the rate of wound healing appears to be accelerated in patients with psoriasis [85, 86]. However, psoriasis can present as lower extremity ulceration, either in isolation or as mixed venous or arterial disease. Treatment should include edema control, topical therapy with anti-inflammatory agents and non-abrasive dressings to avoid triggering the Koebner phenomenon (skin lesions in response to cutaneous trauma) [87]. Because of the risk of infection and malignancy due to immune suppression, systemic or biologic agents should be reserved for those patients with very large lesions that fail to respond to the topical approach [88].

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Naive CD4 + T cell

IL-4

IL-12, IFN-g

TGF-b + IL-6

TGF-b + RA

IL-23

Th1 cell

Th2 cell

Th17 cell

IFN-g, TNF-a

IL-4, IL-5, IL-13,

IL-17, IL-17F, IL-21, IL-22,

Treg cell

TGF-b, IL-10, IL-35

TNF-a, IL-6, GM-CSF Cellular immunc response Organ-specific autoimmunity, intracellular infections Humoral immune response Extracellular parasites. allergic diseases, asthma, atopic disorders

Chronic inflammatory and autoimmunc responses Autoimmunity, infectious diseases, chronic inflammatory disorders

Suppressing effector T cell responses Suppressing autoimmunity, infection

Fig. (2). Differentiation of naïve CD4+ T cells. In response to their environment, naïve CD4+ T cells differentiate into subpopulations and in turn secrete a variety of cytokines that regulate the immune response. Th1 and Th17 (T-helper 1 and T-helper 17 cells are critical in the wound healing response and involved in many inflammatory conditions of the skin. IL-23 produced by dendritic cells and keratinocytes stimulates Th17 cells to produce IL-17A and IL-22, inciting the dermal inflammation characteristic of psoriasis. (Reprinted under CC BY license, Qu et al., 2013 [102]).

Pyoderma Gangrenosum Neutrophil accumulation at the wound site is essential for removal of infectious agents by phagocytosis and for debridement of devitalized tissue [8]. Neutrophils produce antimicrobial agents (reactive oxygen species, cationic peptides, prostanoids and proteases) that help to clean the wound but can induce tissue damage. The neutrophilic dermatoses are a prime example of off-target tissue

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destruction due to unregulated inflammation [30]. Pyoderma gangrenosum (PG), is a neutrophilic dermatosis characterized by painful enlarging necrotic ulcers with an undermined bluish border surrounded by advancing borders of erythema. There is exuberant neutrophil deposition in the dermis. There are several clinical variants of PG including: ulcerative or classic, pustular, bullous or atypical, vegetative, peristomal and drug induced [89]. The fact that there are so many variants, as well as the relatively rare occurrence can lead to treatment delay, incorrect diagnosis and in rare cases amputation. It is a diagnosis of exclusion, requiring a deep skin biopsy to rule out infectious processes including fungal or atypical mycobacterial infections [90]. The most common of the clinical variants is the ulcerative or classic form (Fig. 3a). Classic PG can occur anywhere on the body, but is seem most commonly on the legs. Patients typically feel systemically unwell with symptoms of fever, malaise, arthralgias and myalgias. The lesions commonly present on the lower extremities as a mucopurulent tender ulcer with an edematous, irregular violaceous border with undermined edges. The ulcer often starts off as a papule, or collection of papules, which break down and form an ulcer. The resultant ulcer has been said to have a “cat’s paw” appearance. These will coalesce and the central area will then become necrotic and a single ulcer will result [91]. The lesions heal and scar with a cribiform pattern. Early diagnosis and treatment can help to reduce scarring and disfigurement. Lesions can develop at sites of minor trauma, so surgery and debridement are contraindicated. Peristomal pyoderma comprises approximately 10-15% of all cases of pyoderma and may be a pathergy response to irritation from fecal matter or adhesives from the stoma appliance (Fig. 3b). Most of these patients have inflammatory bowel disease, but peristomal pyoderma can occur in patients who have had an ileostomy or colostomy for malignancy or diverticular disease [92]. The lesions in peristomal pyoderma may be traversed by normal skin, and are typically quite painful. The pain can cause great difficulty when fitting and wearing the stoma appliance. Pustular pyoderma is a rare and superficial variant of the disease (Fig. 3c). It

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begins as a superficial pustule or group of pustules that coalesce and ulcerate. The process stops at the pustular stage, and the patient may have a painful pustule that lasts for several months. Pustular pyoderma usually occurs with exacerbations of inflammatory bowel disease, and tends to be localized to the trunk and extensor surfaces of the limbs [93]. Bullous PG is a superficial variant that affects the upper limbs and face more than the lower limbs. It is usually associated with a hematologic condition. Bullous PG presents as concentric vesicles or bullae that spread quickly in a concentric pattern. They may break down and form superficial ulcers with a bluish border, similar to the classic ulcerations. Prognosis is poor for these patients usually due to underlying hematologic malignancy [94, 95]. Vegetative PG is a superficial form of the disease that is less aggressive than the other varieties (Fig. 3d). It usually occurs with a single lesion in patients who are otherwise well. Vegetative PG usually responds to local treatment more readily than the other forms of the disease. The pathogenesis of PG remains an enigma although it is postulated to be due to neutrophil dysfunction with impaired phagocytosis, abnormal chemotaxis and aberrant integrin oscillations [96]. IL-8 is overexpressed in the ulcers. Approximately 50% of patients with PG have an associated systemic disease, most commonly IBD, arthritis or hematologic diseases [97]. The histopathology in PG depends on the timing of the biopsy as well as the site. Early in the disease, biopsies taken from the erythematous area will show an infiltrate of mature polymorphonuclear leukocytes confined to the dermis. Features of vasculitis may be seen at the edge of the ulcer, with a perivascular lymphocytic infiltrate and fibrinoid necrosis of the dermal vessel wall. Ulceration of the epidermis is secondary to the dermal inflammation. Biopsies taken later in the course of ulcer formation show a polymorphonuclear cell infiltrate with ulceration, infarction and sterile abscess formation [98].

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Fig. (3). Variants of pyoderma gangrenosum. a) Classic pyoderma gangrenosum, b) peristomal pyoderma, c) pustular pyoderma, d) vegetative pyoderma. (Modified from Brooklyn et al. 2006 [91]).

There is no single specific treatment for PG of any subtype. There are few randomized controlled clinical trials. Immunosuppression remains the mainstay of treatment and the most commonly used medications are corticosteroids and

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cyclosporine. Topical therapy with steroids and calcineurin inhibitors is also commonly used. Some of the newer biologics such as infliximab have been used with some success, but treatment remains empirical and usually depends on the experience of the treating clinicians. CONCLUSION The diseases and conditions described above are not exhaustive, but serve to illustrate the complexity and variety of cutaneous responses to inflammatory dysregulation. An overarching theme is that most chronic wounds occur in patients who also have systemic chronic inflammation (Fig. 4).

Th17

IL-22 IL-17 IL-23

Dendritic cells

Pro-inflammatory cytokines Increased proliferation Secretion of chemoattractants

Keratinocytes

TNF

Increased adiposity Metabolic dysregulation

Adipocytes

Adhesion molecules

Endothelium

Fig. (4). The central role of TNF in chronic inflammatory disease. Elevated TNF plays a central role in metabolic and inflammatory skin disease, suggesting a unifying hypothesis with a specific target for therapeutic modulation. (Reproduced under CC BY license, Yost and Gudjonsson 2009 [81]).

Thus there is substantial evidence for at least an association with metabolic syndrome although there is not yet sufficient evidence to show cause and effect of either the skin disease causing metabolic syndrome or vice versa [27, 99, 100].

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Better understanding of the mechanisms whereby inflammatory processes become dysregulated will facilitate development of targeted therapies that will promote healing and reduce the morbidity and mortality of chronic wounds. CONFLICT OF INTEREST The authors confirm that they have no conflict of interest to declare for this publication. ACKNOWLEDGEMENTS Declared none. REFERENCES [1]

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CHAPTER 5

Metabolic Regulation of Inflammation Chang-An Guo1, Laura Bond1, James M. Ntambi1,2,* 1

Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA

2

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA Abstract: Inflammation and the related immune responses are energetically expensive processes, defending against pathogens and maintaining tissue homeostasis. As a result, immune response and metabolic regulation are highly integrated, allowing organisms to adapt to changes in their internal and external environments. Many nutrient- and pathogen-sensing system share common signaling pathways and have been evolutionarily conserved. Studies over the past decade have demonstrated that inflammation is a key feature of obesity, type 2 diabetes, and various cardiovascular disease states. In the context of over nutrition, shifts in tissue metabolism are accompanied with waves of profound recruitment of inflammatory cells (monocytes and lymphocytes) and high proliferation rates among lymphocyte populations. In this chapter, we review recent work addressing metabolic control of inflammation and immunity as well as the molecular aspects of metabolic inflammation converging to insulin resistance. It is crucial to explore the question of causality between the state of chronic inflammation and metabolic dysfunctions seen in obesity, and therefore developing effective therapeutic strategies to cope with the current worldwide obesity epidemic.

Keywords: Immune cell, Inflammation, Insulin resistance, Metabolism, Obesity, Over nutrition. INTRODUCTION The ability to withstand starvation and to fight off infections is critical for species survival. Metabolism fuels all biological programs including development, Address correspondence to James M. Ntambi: University of Wisconsin-Madison; 433 Babcock Dr, RM 415B, Madison, WI 53706, USA; Tel: 608-265-3700; Fax: 608-265-3272; Email: [email protected] *

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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proliferation and differentiation. The immune system continually senses and responds to environmental challenges, a process that is powerful and energetically demanding. It is now appreciated that immune response and metabolic regulation are highly intertwined and evolutionarily conserved processes, therefore, proper function of one is dependent on the other. One example that represents this active interaction is the Drosophila fat body, which incorporates the mammalian homologs of the liver, adipose tissue, and the hematopoietic immune system into one functional unit [1, 2] The fly’s fat body carries out a crucial function in sensing energy availability and coordinates the responses to pathogen with metabolic status [1]. It is very possible that, in the fly, common and overlapping molecular pathways regulate both metabolic and immune functions and in higher organisms, tissues or organs that are responsible for metabolism and immunity maintain their developmental heritage. As such, it is conceivable that in the context of obesity epidemic, nutrient surplus might be able to activate a pathogen-sensing system, such as the Toll-like receptors (TLRs) and NOD (nucleotide-binding oligomerization-domain protein)-like receptors (NLRs) [3], and nutritionally induce inflammatory responses. INFLAMMATION AS A LINK BETWEEN OBESITY AND METABOLIC SYNDROME Metabolic syndrome, also known as Syndrome X or insulin resistance syndrome, is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease, stroke, and type 2 diabetes. Gerald Reaven, in his 1988 Banting lecture, described “Syndrome X” as the association of insulin resistance, hyperglycemia, hyperinsulinemia, hypertension, low HDL cholesterol and elevated VLDL triglycerides [4]. Today, obesity, especially abdominal obesity or central obesity, has been added to the list and considered to be one of the most important criteria for evaluating metabolic syndrome. In the past two decades, the search for a unifying mechanism behind the pathogenesis of obesity-associated metabolic syndrome has revealed a close relationship between nutrient excess and an alternative form of inflammation,

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called “metabolic inflammation” or “metainflammation”, which is characterized by the chronic, low-grade inflammation that is observed in obesity [5]. Appreciation of the involvement of inflammation in insulin resistance or type 2 diabetes started with the use of salicylate. In 1876, Wilhelm Ebstein first demonstrated that high doses of sodium salicylate could diminish glycosuria in diabetic patients [6]. Consistently, in 1901, R. T. Williamson reported that “sodium salicylate had a definite influence in greatly diminishing sugar excretion” [7]. However, the hypoglycemic actions of salicylates and the molecular target of salicylates, IκB kinase-β (IKKβ)/NF-κB axis [8, 9], were certainly not known at the time. The association between insulin resistance and inflammation was later recognized with the identification of insulin resistance in patients with sepsis [10]. We now know that many diseases with active inflammatory responses display insulin resistance as a feature, including hepatitis C, HIV, and arthritis [11 - 13]. Direct proof of the link between inflammation and metabolic responses came from the genetic studies in mice by Hotamisligil and colleagues. They found that adipose tissue from obese mice secretes inflammatory cytokines (such as TNFα) and that these cytokines themselves can inhibit insulin signaling [14, 15] (Fig. 1). CLASSIC INFLAMMATION VS. METABOLIC INFLAMMATION Inflammation is usually referred to as classic acute inflammation, an adaptive response to harmful stimuli, such as infection, tissue injury and irritants. Acute inflammation is a protective attempt by the organism to remove the injurious stimuli, followed by a resolution and repair phase to restore homeostasis. The classic response of acute inflammation is a short-term and high-amplitude process, usually appearing within a few minutes or hours and resolving upon the removal of the injurious stimulus. Acute inflammation is characterized by five cardinal signs: pain, heat, redness, swelling and loss of function [16]. Despite sharing similar pathways and mediators, inflammation induced by metabolic surplus or the so called “meta-inflammation” is distinctive and is not caused by the classic instigators of inflammation: infection or injury [17]. Instead, this altered form of inflammation is associated with the malfunction of tissues that

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are not directly related to host defense or tissue repair. First, the trigger of metabolic inflammation is different. In obesity-related metabolic syndrome, metabolic signals emerging from metabolic cells, such as adipocytes or hepatocytes, induce inflammatory responses and deteriorate metabolic homeostasis. An array of inflammatory cytokines is increased in the obese adipose tissue (and in adipocytes themselves), including TNFα, IL-6, IL-1β, CCL2, MCP-1, SAA and many others [18]. The activation of TLR4 on hepatocytes by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) or endogenous ligands (e.g., free fatty acids) also contributes to inflammation in obesity [19]. In addition to adipose tissue and liver [20], pancreas [21], brain [22] and muscle [23] all possibly contribute to the elevated systemic inflammation in the obese state. Importantly, the obesity-associated inflammation discussed here, though significant, is often modest when compared with that of an infection or trauma. Second, the duration of metabolic inflammation that occurs in obesity is vastly different from the duration of acute inflammation. Contrary to classic acute inflammation, in obesity, the increased inflammatory cytokine expression that occurs in various metabolic tissues and organs appears to happen gradually and remains unresolved over time. Several studies carefully examined the timing of obesity-induced inflammation in mice. One group reported that increases in inflammatory and macrophage-specific gene expression in adipose tissue occurred after 3-week of high-fat diet (HFD) feeding, with a more dramatic increase at 16 and 26 weeks on the same diet [24]. Thus, it seems that the inflammation induced by nutritional overload, unlike acute inflammation, is not dramatic enough to mount a full resolution program, therefore the low-grade inflammation is maintained in a chronic manner for months and years. This lack of resolution may be due to the lack of evolutionary selection to develop such a response against chronic energy surplus. MOLECULAR PATHWAYS THAT LINK INFLAMMATION AND INSULIN RESISTANCE Obesity-associated tissue inflammation is now recognized as a major cause of

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decreased insulin sensitivity. How inflammatory signals disrupt insulin action in obesity has been an intensive area of research. As demonstrated in the Fig. (1), insulin receptors acquire docking proteins, insulin receptor substrates (IRS), to propagate downstream signaling cascades [25]. The tyrosine phosphorylation of IRS is a crucial step in insulin signaling and is inhibited by counter-regulatory serine/threonine phosphorylation [26]. IRS tyrosine phosphorylation is often defective in many cases of insulin resistance [27]. IRS-1 can also be phosphorylated at inhibitory serine residues by a variety of kinases, such as JNK, IKKβ, S6 Kinase, mTOR and protein kinase C (PKC) and this serine phosphorylation on IRS-1 blunts insulin signaling [28 - 30]. Insulin

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Fig. (1). Signal transduction in insulin action The insulin receptor tyrosine kinase undergoes autophosphorylation when bound to insulin on the outer surface of the plasma membrane, which transduces its signal to IRS proteins. The cytoplasmic signaling starts with tyrosine phosphorylation of IRS, which leads to a diverse series of signaling pathways including the activation of PI3K, MAP kinase and AKT. These pathways act in a coordinated fashion to regulate vesicle trafficking, protein synthesis, and gene expression.

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In response to various metabolic stresses that occur in obesity, JNK [28], IKK [31] and PKC [32] are often activated, which inhibits insulin action (Fig. 1). Specifically, JNK activity increases dramatically in critical metabolic sites of obesity [33], such as adipose tissue, liver, and hypothalamus [34]. Upon exposure to cytokines, free fatty acids, reactive oxygen species, or endoplasmic reticulum (ER) stress, JNK is acutely activated [28, 35], which contributes to obesityinduced insulin resistance. These observations were validated by the characterization of JNK1-/- mice. JNK1 deficiency protected mice from IRS-1 serine phosphorylation, and improved systemic glucose homeostasis and insulin sensitivity [36]. IKKβ is another inflammatory kinase that is critical in the development of insulin resistance. As mentioned earlier, high dose salicylates administration improves insulin action by inhibiting IKKβ kinase activity [9]. Experimental activation of IKKβ in the liver is sufficient to cause systemic insulin resistance [20]. Protein kinase C has various isoforms and is important for the interaction between inflammatory and metabolic pathways. PKC is thought to be downstream of lipid signals [37, 38]. Intermediate metabolites of lipid biosynthesis, such as fatty acylCoA, diacylglycerol (DAG), and ceramides may activate PKC-θ in muscle and PKC-δ in the liver, which eventually inhibits insulin action [39]. PKC-θ knockout mice are protected from obesity-induced insulin resistance, confirming the contribution of this kinase to metabolic regulation in vivo [38]. In addition to increasing IRS-1 serine phosphorylation, the inflammatory kinases also exert their effects through regulation of gene expression. JNK, ERK1/2 and p38 MAPK can activate transcription factors, such as activator protein-1 (AP-1) and NF-κB, which subsequently induce expression of key inflammatory genes [40]. When NF-κB pathways are activated, more inflammatory cytokines and chemokines, such as TNFα, IL-6, IL-1β and MCP-1 are produced, which further activates JNK, IKKβ, and PKC and establishes a stable, feed-forward signaling loop. Other mechanisms that link inflammation with insulin resistance may include suppressor of cytokine signaling (SOCS) proteins, which are involved in the degradation of IRS-1 [41], as well as organelle dysfunction [42].

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RESIDENT AND INFILTRATED IMMUNE CELLS IN ADIPOSE TISSUE One of the first organs influenced by nutritional excess is the adipose tissue, which can communicate with other peripheral tissues through the release of adipokines, cytokines and fatty acids; thereby having effects on systemic inflammation and insulin sensitivity. Genetic manipulations within adipocytes that enhance local insulin sensitivity often improve systemic insulin sensitivity and glucose homeostasis [43 - 46], indicating a critical role of adipose tissue in whole body glycemic control.

Lean

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CD8+ T cells CD4+/TH T cells Tregs T cells NKT T cells

Eosinophils Mast cells B cells

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Fig. (2). Infiltration of pro-inflammatory immune cells into WAT is a hallmark corollary of obesity. In the lean state, M2 macrophages and Tregs reside in WAT and produce anti-inflammatory cytokines. With overnutrition and adipocyte hypertrophy, distinct immune cells are recruited to WAT and secrete proinflammatory cytokines. These cytokines can act locally in WAT or be released into the bloodstream to elicit a full body chronic immune response.

One hallmark of the inflammatory state of obesity is increased immune cell infiltration into metabolic tissues, especially, white adipose tissue (WAT) (Fig. 2). Several types of stresses such as endoplasmic reticulum (ER) stress, oxidative stress and hypoxia are associated with adipose tissue expansion [42]. All of these

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cellular stresses result in the production of chemokines and proinflammatory cytokines, such as MCP-1, IL-6 and TNFα. The proinflammatory environment of obese adipose tissue activates not only resident leukocytes but also creates a chemotactic gradient that further attracts various inflammatory cells from the circulation [47 - 50]. Macrophages Macrophages, the sentinels of innate immunity, reside in almost every tissue in the body, where they contribute to various homeostatic functions in addition to host defense. An important discovery that helped to elucidate the cause of tissue inflammation was that adipose tissues from obese animals and humans are infiltrated by large numbers of macrophages [50]. These cells display remarkable heterogeneity in their cell surface markers. By flow cytometry, macrophages are defined as F4/80+/CD11b+ cells. In the progression of weight gain from lean to obese, macrophage content increase from approximately 10% of all adipose tissue cells to over 50%. Adipose tissue macrophages (ATMs) in lean and obese animals have different inflammatory potential along with distinct surface markers and cytokine signatures. In lean adipose tissue, macrophages are mostly alternatively activated M2-polarized macrophages, which are characterized by the presence of surface marker, CD206 (mannose receptor) and macrophage galactose-type C-type lectin 1 (MGL1), and can be further subdivided into M2a, M2b and M2c cells [51, 52]. M2 macrophages in lean adipose tissue produce anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonist (IL-1Ra) [53, 54]. However, obesity swaps macrophage population from an immunoregulatory M2 phenotype towards a proinflammatory M1 bias. In obese adipose tissue, M1-polarized macrophages known as classically activated macrophages express CD11c (integrin alpha X chain protein), with diminished CD206 and MGL1 expression. M1 cells also express high levels of iNOS and proinflammatory cytokines (TNFα, IL-1β and IL-6). These cytokines can act locally in a paracrine manner, or they can leak out of the adipose tissue and have systemic effects, decreasing whole body insulin sensitivity [55 - 57]. To investigate the function of M1 polarized macrophages in obesity-inflammation response, CD11c immune cells were selectively depleted in

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mouse via a conditional cell ablation system that is based on transgenic expression of the diphtheria toxin receptor under the control of CD11c promotor. CD11c depletion resulted in reduced macrophage numbers as well as reduced adipose tissue inflammation and improved insulin sensitivity in the diet-induced obese mice [58]. Microarray analysis of M1 and M2 macrophages revealed that genes important for fatty acid oxidation were preferentially expressed in M2 macrophages, postulating that distinct substrates and pathways might meet the metabolic demands of various macrophage cell types [59]. It is important to note that tissue macrophages rapidly respond to perturbations of energy homeostasis by constantly altering their transcriptional programs, thus, ATMs may actually represent a phenotypic spectrum. The M1/M2 classification described here is very likely an oversimplified view of more dynamic macrophage populations that are present in the adipose tissue. For instance, costimulation blockade of CD40CD154 signaling pathways has long been an attractive strategy to depress macrophage activity, therefore inhibiting T cell activation in complications like autoimmune diseases, transplantation and allergies [60, 61]. However, recent studies suggested that CD40 deficiency, in fact, exacerbates obesity-induced adipose tissue inflammation by increasing M1 macrophage and CD8+ T cell infiltration [62, 63]. Furthermore, loss of Stearoyl CoA desaturase 1 (SCD-1) in adipose tissue attenuates adipocyte inflammation and reduces macrophage activation [64], however, SCD-1 deficiency in the skin causes marked sebaceous gland hypoplasia as well as the accumulation of M1 macrophage [65, 66], suggesting that macrophage activation status in response to the CD40 or SCD-1 deficiency depends on the specific local microenvironment. In general, most adipose macrophages are thought to originate from bone marrow-derived monocytes, which infiltrate adipose tissue from circulation. However, a recent study has shown that macrophages can undergo significant cell division within visceral and subcutaneous adipose tissues of obese mice, suggesting that in situ proliferation might also be an important mechanism by which ATMs accumulate [67]. Lymphocytes Other than macrophages, studies have revealed a growing list of immune cells that

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infiltrate obese adipose tissue. T cells, as one subset of lymphocytes have been shown to infiltrate adipose tissue during obesity. In 2009, three independent studies demonstrated the critical role of T cells in adipose tissue for the regulation of insulin sensitivity in genetic or dietinduced obese mouse models [68 - 70]. Within the adipose microenvironment, the direct or indirect interactions between T cells and adipocytes may be multifaceted. Multiple cytokines and chemokines may regulate lymphocyte recruitment to the WAT. One such protein is RANTES (known as regulated upon activation, normal T cell expressed and secreted), which is secreted by murine and human adipocytes as well as stromal vascular fraction (SVF) cells and may promote the accumulation of lymphocytes into WAT via binding to their receptor CCR5 [71]. Similar to RANTES, the interaction between IFNγ inducible protein-10 (IP10), which is expressed by adipocytes [72], and its receptor CXCR3, which is present on T cells, can alter the balance between effector T cells and regulatory T cells (Tregs) [73] and contribute to the recruitment of T cells into adipose tissue [74]. Furthermore, lymphocytes may modulate adipocyte cytokine secretion via the activation of the CD40–CD40L dyad and vice versa [75]. Distinct T cell subtypes play different roles in the course of obesity-related adipose tissue inflammation. T cells that express the surface marker CD8, referred to as effector, or cytotoxic T cells secrete proinflammatory cytokines. A study by Nishimura and colleagues has demonstrated that CD8+ T cell infiltration precedes that of macrophages during HFD feeding, and this T cell subset promotes the recruitment and activation of ATMs [68]. In addition, overweight individuals contain a higher proportion of CD8+ cells in visceral adipose tissue compared with subcutaneous adipose tissue, and the percentage of CD8+ cells is positively correlated with the activity of caspase-1, which is a component of the NLR pyrindomain-containing 3 (NLRP3) inflammasome [76]. T helper (TH) cells express the surface marker CD4 and can be divided into three subpopulations: TH1, TH2 and TH17 cells. TH1 cells produce proinflammatory cytokines (such as IFNγ), and TH2 cells produce anti-inflammatory cytokines (such as IL-4, IL-10 and IL-13) [77]. The TH17 subpopulation was recently identified and produces IL17 [78].

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In obesity, adipose tissue-associated lymphocytes undergo reorganization, exchanging small TH2 cell dominated repertoire (associated with lean phenotype) with much larger and more inflammatory TH1 and CD8+ cell dominated population [69]. This change leads to a progressively proinflammatory environment promoting insulin resistance. RAG1-/- mice lack T lymphocytes and have increased body weight and increased insulin resistance compared with wildtype mice. After adoptive transfer of CD4+, but not CD8+ T cells, these trends were reversed [69]. These results suggest that metabolic dysfunction caused by obesity is at least partially mediated by CD4+ cells, and that the imbalance between TH1 and TH2 cells in the WAT may represent a pathophysiological component of obesity and insulin resistance. Another CD4+ T cell population, Tregs, express forkhead-winged-helix transcription factor (Foxp3) and are characterized as CD4+/CD25+/Foxp3+ cells. Tregs secrete anti-inflammatory signals that inhibit macrophage migration and induce the beneficial M2-like macrophage differentiation. These cells are considered to be important players in obesity-related adipose tissue inflammation. The number of adipose tissue Tregs decreases with obesity [70, 79, 80], whereas adoptive transfer of Tregs improves WAT inflammation and ameliorated insulin resistance in ob/ob mice [80, 81]. Natural Killer T (NKT) cells represent a heterogeneous T cell subpopulation with innate-like characteristics and are capable of producing both TH1 and TH2 cytokines [82]. The role of NKT cells in obesity-related inflammation is not entirely clear. On one hand, adoptive transfer of NKT cells improves nonalcoholic steatohepatitis and glucose intolerance in ob/ob mice [83]; on the other hand, NKT-deficient mice (β2-microglobulin knockout mice) on HFD display reduced macrophage accumulation in the adipose tissue and better glucose tolerance compared with control mice [84]. Further investigations are required to elucidate the role of NKT cells in obesity-associated inflammation. B cells, the producers of antibodies, can also accumulate in the WAT of HFD-fed obese mice [85]. Some studies have reported that B cells infiltrate into the WAT earlier than T cells or macrophages and prior to the appearance of insulin resistance [86]. B cell-mediated effects on glucose metabolism are linked to

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proinflammatory macrophages and T cell activation [87]. Furthermore, B cells can cause systemic insulin resistance through the production of pathogenic IgG autoantibodies [85]. Mast Cells and Eosinophils Mast Cells are involved in early leukocyte recruitment and adaptive immunity via activation of antigen presenting dendritic cells. In response to different signals, mast cells can secrete a wide spectrum of biologically active products, such as serine proteases, histamine, serotonin, leukotrienes and thromboxane with either pro- or anti-inflammatory properties [88]. In 1963, Hellman and colleagues found that there were increased numbers of mast cells in both epididymal and subcutaneous adipose tissue of obese, diabetic mice, suggesting a potential role for mast cells in obesity [89]. This role of mast cells was confirmed by a recent study that described that genetic depletion or pharmacological stabilization of mast cells in mice reduced weight gain and ameliorated glucose homeostasis [49]. Eosinophils are associated with parasite immunity or allergy and can regulate obesity-associated adipose tissue inflammation by modulating macrophage polarization. This particular cell type was recently found to assist in glucose homeostasis by maintaining anti-inflammatory M2 macrophage content in WAT [90]. In this study, eosinophils within WAT were identified as the main source of IL-4 and IL-13, which contribute to the anti-inflammatory phenotype of macrophages. In the absence of eosinophils, M2 macrophages content was greatly attenuated [90]. Interestingly, migratory helminth-induced adipose tissue eosinophilia enhances glucose tolerance in HFD-fed obese mice [90]. THERAPEUTIC OPPORTUNITIES FOR METABOLIC DISEASES Anti-Inflammation Therapeutics Since chronic inflammation in obesity causes adverse metabolic effects in various tissues, it is natural to raise the question of whether therapeutic interventions that modulate inflammatory signaling cascades could have beneficial effects on metabolism. Several previous and ongoing studies have targeted inflammation at different points of the inflammatory pathway in obesity.

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As described above, salsalate, a salicylate prodrug, suppresses IKKβ/NFκB activity and improves glycemic control as well as lipid parameters in type 2 diabetic patients [91, 92]. Studies involving JNK antagonists, tested in mice, yielded positive results in glucose metabolism [93]. Inflammatory cytokines blockade also showed promising results on metabolic disease. Although antiTNF-α trials yielded conflicting results [94, 95], IL-1 receptor antagonists (anakinra) improved hyperglycemia and β-cell function and decreased systemic inflammatory markers [96]. Cell-based immunotherapy targeting obesity inducedinflammation has recently attracted attention. Several animal studies demonstrated significant metabolic benefits because of depletion or stimulation of specific cell populations. For example, as discussed above, elimination of CD11c+ immune cells or mast cells in obese mice yielded beneficial metabolic effects [49, 58]. These studies provide proof-of-principle that damping the inflammatory component of obesity can disrupt the link between obesity and insulin resistance, results in improved insulin sensitivity in mice and humans. Reverse the Imbalance of Excess Caloric Intake and Energy Expenditure: A Second Thought The root cause of the current worldwide epidemic of obesity and type 2 diabetes lies in the positive energy balance in individuals. Due to increased food availability, high energy density of food content, intestinal dysbiosis and sedentary lifestyle, 1.5 billion people on the earth are now overweight or obese. There is no doubt that insulin resistance is a key factor in the generation of type 2 diabetes and numerous studies have provided solid evidence that decreasing chronic inflammation in obesity ameliorates insulin sensitivity and brings beneficial effects on glycemic control of diabetic individuals. However, it is well established that insulin is the major anabolic physiological agent and master regulator of energy storage [97]. The release of insulin from pancreatic β cells increases glucose, amino acid, and fatty acid uptake and storage, and also blocks breakdown. Indeed, many of the most widely used insulin-sensitizing pharmaceuticals are associated with an increase in adiposity rather than a decrease [98], suggesting that simply mimic insulin action, including anti-inflammation strategy

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may not fundamentally address the problem of obesity epidemic. Nowadays, researchers are starting to appreciate that inflammatory insulin resistance is actually an intrinsic adaptive trait of organisms against sustained over nutrition, therefore, inflammation in obesity can be an advantageous mechanism, which favors energy mobilization rather than storage [99]. Appreciation of the beneficial effects of insulin resistance against obesity has led researchers to reconsider the therapeutic potential of insulin-sensitizing treatment as a major way to treat metabolic dysfunctions. New approaches are needed to block energy storage and allow energy mobilization. Currently, emerging therapeutics aiming to fundamentally reverse energy imbalance in obesity by prompting basal metabolic rate are underway. Amlexanox, a high-affinity inhibitor of IKKε/TBK1 and an approved small-molecule drug presently used in the clinic to treat aphthous ulcers was found to be able to stimulate energy expenditure via increased thermogenesis [100]. Several naturally occurring hormones leading to the “browning” of white adipose tissue, such as irisin [101], meteorin-like (Metrnl) [102], and tumor-derived parathyroid-hormone-related protein (PTHrP) [103] were recently identified. These novel obesity-combating approaches are more likely to target the energetic imbalance that underpins the state of obesity. CONCLUSION Although it is clear that inflammation elicited by severe infection or trauma renders metabolic deterioration, whether the same is applicable to chronic metabolic disorders is still under debate. Recent research has elucidated many of the mediators and mechanisms that are involved in inflammation-associated metabolic disease, opening up the possibility of treating obesity-associated complications with immunomodulatory strategies. In the setting of positive energy balance, it is likely that metabolic signals trigger inflammatory responses, which then further impairs metabolic function, leading to more stress, chronic inflammation and a feed-forward loop. To manipulate the interface between complex immunity and metabolism pathways for therapeutic purposes, it is essential to understand the causality of metabolic inflammation and to identify signals that initiate inflammation or mediate recruitment of inflammatory immune cells to

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major metabolic tissues, such as adipose tissue and liver. New approaches aiming to block energy storage or promote energy utilization combined with anti-inflammation therapy may provide tailored therapeutic opportunities to individuals. CONFLICT OF INTEREST Chang-An Guo is supported by ADA (7-13-BS-118); Laura Bond is supported by NIH National Research Service award & 32 GM07215. Dr. Ntambi has support from the ADA (7-13-BS-118) as well as USDA (Hatch W2005). No reports of conflicts of interest by the authors. ACKNOWLEDGEMENTS The authors would like to acknowledge Lucas O’Neill and Sabrina Dumas for their generous edits to this chapter. REFERENCES [1]

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CHAPTER 6

Aging and Inflammation Daipayan Banerjee, Alexander A. Karakashian, Mariana N. NikolovaKarakashian* Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA Abstract: Inflammaging is a term referring to the constitutive low-grade inflammation that underlies the process of aging. The causes of inflammaging stem from an upregulation of the innate and a decline in the adaptive immune systems and involve chronic induction of the production of inflammatory mediators, including cytokines, chemokines, and bioactive lipids. Damaged DNA and protein that accumulate in the cells of the aging organisms, oxidative stress, and changes in the function of adipose tissue are among the key culprits leading to the onset of inflammaging. Changes in cytokine signaling pathways at cellular levels also occur with aging, contributing to propagation of inflammation. The inflammaging is considered the main contributing factor to the development of various aging-associated diseases, including cancer, atherosclerosis, metabolic, and neurodegenerative diseases. At least in animal models, inflammaging is subdued by common anti-aging therapies like caloric restriction and resveratrol.

Keywords: Adipose tissue, Bioactive lipids, Caloric restriction, Ceramide, Cytokine signaling, Inflammaging, Innate immune response, Interleukin 1, Oxidative stress, Resveratrol, Senescence, Tumor necrosis factor. INTRODUCTION In 350 B.C, Aristotle wrote: “It remains for us to discuss youth and age, and life and death. To come to a definite understanding about these matters would complete our course of study on animals”. Understanding the matters of old age is Address correspondence to Mariana N. Nikolova-Karakashian: University of Kentucky College of Medicine; Department of Physiology, MS508, 800 Rose Str. Lexington, KY, 40536; Tel: (859)323-8210, Fax: (859) 323-1070; Email: [email protected]

*

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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far from complete. We are still trying to determine the fundamental causes of aging and what the maximum possible life span of the human species is. Nevertheless, the concept that aging and inflammation are intrinsically interwoven has become a centerpiece of contemporary gerontology and geriatrics. This is based on two complementary doctrines: immunosenescence and inflammaging. The latter is considered key factor behind numerous serious diseases associated with old age. Immunosenescence The term immunosenescence is strictly defined as a decline in the adaptive immune response of the host in response to antigenic challenge. It is exemplified by changes in T-cell subpopulation size, cell-intrinsic defects in B-cells, abnormal secretion patterns of several cytokines, and decreased antibody production [1]. The causes for the impairment of the adaptive immune system in the elderly are not entirely clear. Replicative senescence of hematopoietic stem cells, adaptation of the immune system to persistent intrinsic and extrinsic challenges, and intrinsic de-regulation of signaling pathways via changes in the lipid rafts, are just some of the proposed causes for the onset of immunosenescence [2]. Regardless the cause, this decline in the adaptive immunity is directly linked to increased susceptibility of the elderly to infectious diseases, as well as poor response to vaccination and increased infection-related mortality and morbidity. The elevated incidence of cancers in the elderly is also linked to some extent to the reduced immunosurveillance for cancerous cells [3]. Somewhat paradoxically, age-related immuno-senescence has also been linked to increased autoimmunity (the loss of self-tolerance) in the elderly. Finally, the onset of a state of chronic low-grade inflammation in the elderly has been suggested to be at least in part, the result of declining adaptive immune system. Inflammaging The state of perpetual low-level inflammation is another characteristic of the aging process and is often referred to as “inflammaging”, a term coined in 2000 by Franceschi et al. [4]. It is thought to contribute to a plethora of degenerative illnesses, including cardiovascular diseases, neurodegenerative syndromes, and

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cancer as well as ailments such as muscle cachexia. While immunosenescence refers to the decline in the adaptive component of the immune system, inflammaging is a loosely defined term that denotes an increased activity and hyperresponsiveness of the innate arm of the immune system. Inflammaging is associated with subtle increases in local and/or systemic concentrations of inflammatory markers. Those include pro-inflammatory cytokines, chemokines, acute phase proteins, and bioactive lipids. The process is accompanied by intrinsic, cell autonomous changes in the cellular response to inflammation, typically in the direction of hyperresponsiveness. The probable cause for this hyperresponsiveness is age-related changes in the cytokine signaling pathways that cause hyper-sensitization of cells to even small amounts of agonists (amounts that typically have no effect in young organisms) resulting in propagation of proinflammatory signaling. All this contributes to the onset of tissue inflammation and to the increased incidence of aging-associated diseases. While immunosenescence certainly has a role in the onset of inflammaging, numerous other factors are also essential. These include: changes in the neuroendocrine axes, increased oxidative stress, intrinsic changes in the TLR signaling cascades in various cell types, metabolic stress, and the inability of cells to repair and clear damaged cellular components (like DNA, protein, and lipids). Although the exact causes of inflammaging may be debatable, the link to various agingassociated diseases like cancer, Alzheimer’s, and cardiovascular disease is not. Many of the proposed anti-aging remedies such as caloric restriction, resveratrol supplementation, and others seemingly subdue the pro-inflammatory state in the elderly in parallel to a decreasing incidence of some aging-associated diseases. Significant research efforts are currently targeted at furthering our understanding of the association between inflammaging and disease, as well as elucidating the fundamental reasons for the onset of inflammaging. The goal of this chapter is to summarize the current knowledge regarding the causes, manifestation, and consequences of the state of inflammaging in the elderly, focusing on changes related to the innate immune system.

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BIOLOGICAL AND MOLECULAR BASIS FOR AGING-ASSOCIATED CHRONIC INFLAMMATION Introduction In healthy young individuals, inflammation is a complex host defense mechanism against insult and stress (both physiological and non-physiological), resulting from chemicals, drugs, oxidants, and a variety of microbial organisms. It orchestrates the healing and tissue repair process. Pathogen-associated molecular patterns (PAMP) and damage-associated molecular patterns (DAMP) activate a series of cell surface and intracellular receptors, leading to the secretion of proinflammatory cytokines. Cytokines initiate and regulate the so-called acute phase response (APR), which is comprised of a wide range of immediate local events at the site of inflammation, as well as activation of systemic features. The response includes increased secretion of liver-derived acute phase proteins, fever, and granulocytosis. This complex cascade is designed to isolate and destroy microbial pathogens, and to activate the tissue repair processes that would eventually facilitate the return to homeostasis. Interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) are the earliest mediators of APR and in turn induce a second wave of cytokines, including IL-6 and chemokines. IL-6 is an important immunoregulatory cytokine required for controlling local and systemic inflammatory responses while chemokines regulate the influx of leukocytes to the site of inflammation. In addition to transcriptional and post-translational regulation, TNFα and IL-1β bioactivity is also controlled by naturally occurring antagonists such as IL-1 receptor antagonist, and soluble TNF receptors as well as by the antiinflammatory cytokine IL-10. In older people and animals however, a state of chronic low-grade inflammation is a characteristic feature that is persistent even in the absence of any significant external insults [5 - 10] (sometimes called sterile inflammation). This underlying inflammation in the elderly is considered the main cause for elevated incidence of various diseases, including cancer, Alzheimer’s disease, atherosclerosis and diabetes. Therefore, understanding the true nature of this chronic inflammatory state and the mechanisms responsible might be key in improving the quality of life of elderly, if not life expectancy per se. According to the “inflammation

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hypothesis of aging” [11], a chronic increase in the basal levels of a variety of different inflammatory markers occurs with age, and this affects not only the basal homeostasis of different organs, but also the response to environmental challenges. Changes have been reported in the cardiovascular system [10], macrophages [6, 9, 12], liver [13 - 16], adipose tissue [17] and brain [8, 16, 18]. Furthermore, changes at the cellular levels leading to hyper-sensitization or hyper-responsiveness towards some cytokines have also been observed and would serve to amplify and propagate a pro-inflammatory environment in the elderly. Changes in the Basal Levels of Systemic Inflammatory Mediators in Human and Rodents during Aging The systemic low-grade inflammation associated with aging is characterized by subtle increases in the concentration of some cytokines, acute phase proteins, and other inflammatory mediators, in the absence of underlying infection [19]. Despite numerous studies in humans, mice and rats, whether and by how much the basal levels of key inflammatory markers change is still subject to controversy. While some studies in humans have seen statistically significant changes in the levels of TNFα with age [20], others have not [21]. Similar uncertainty exists in respect to IL-1β levels. Early in 1993, while investigating a cohort of 33 healthy elderly subjects, the Rosenstreich group reported a very substantial increase in the urine IL-1β concentrations. In 85% of the subjects, the levels of IL-1β were elevated (an average of 0.88 U/ml) compared to the normal levels of less then 0.05 U/ml for young adults. Mean urine protein and creatinine levels did not differ significantly, indicating that the changes were specific for IL-1β [22]. Another comprehensive study on 595 men and 748 women from the general population showed that the plasma levels of IL-1β are similar in aged and young individuals [21]. Differences in the nutritional and activity status of enrolled subjects, as well as possible existence of non-diagnosed illnesses could explain the discrepancies regarding the effects of aging on these pro-inflammatory cytokines in humans. Studies on other inflammatory markers have yielded more coherent results. The Bauer group, for example, reported a linear correlation between IL-6 and age in healthy individuals (23-87 years) with an annual increase of 0.016 pg/ml [23]. Forsey et al. [19] and Ferrucci et al. [21] confirmed the aging-associated elevation

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in IL-6 plasma levels, and also reported significant increases in the intercellular adhesion molecule-1, TGF-β [19], IL-1 receptor antagonist, IL-18, the C-reactive protein (CRP), and fibrinogen [21] (Table 1). The onset of a state of chronic inflammation during aging has been better delineated using different rodent models. Studies by the Effros group using young and old mice (8-14 and 28-36 months old) found significant aging-associated increase in the serum levels of TNFα and IL-6 (from 40±5 pg/ml to 340±115 pg/ml and from 123±83 pg/ml to 434±214 pg/ml respectively) [7]. In rats, the levels of IL-1β have been reported to increase from 64±11 pg/ml in 3 months-old Wister rats to 192±55 pg/ml in 24 months-old ones [24]. Serum IL-6 and CRP levels also significant increased in older rats as compared to young ones. Increases in CRP levels are also found in old mice. Table 1. Aging-associated changes in the levels of some cytokine and acute phase proteins levels. Marker

Tissue

Young/Middle Age

Aged

TNFα

Plasma

7.8±0.5 pg/ml

12±0.9 pg/ml

Human

[20]

IL-6

Plasma

7.2±.4 pg/ ml

10±1.2 pg/ml

Human

[20]

IL-6

Plasma

0.34 ± 0.39 pg/ml

1.05 ± 0.77 pg/ml

Human

[23]

IL-6

Plasma

0.4 to 0.8 pg/ml

2.6 to 4.7 pg/ml

Men

[21]

IL-6

Plasma

0.5 to 0.8 pg/ml

1.7 to 2.6 pg/ml

Women

[21]

IL-1β

Plasma

0.10 to 0.15 pg/ml

Men

[21]

IL-1β

Plasma

0.12 to 0.18 pg/ml

0.11 to 0.17 pg/ml

Women

[21]

IL-1ra

Plasma

100 to 125 pg/ml

131 to 180 pg/ml

Men

[21]

IL-1ra

Plasma

96 to 135 pg/ml

130 to 160 pg/ml

Women

[21]

IL-18

Plasma

303 to 369 pg/ml

417 to 493 pg/ml

Men

[21]

IL-18

Plasma

245 to 292 pg/ml

392 to 470 pg/ml

Men

[21]

IL-1β

Urine

2.5 pg/ml

57.4 pg/ml

Human

[22]

CRP

Plasma

0.8 to 1.4 g/L

3.8 to 7.9 g/L

Men

[21]

CRP

Plasma

0.8 to 1.5 g/L

2.6 to 4.3 g/L

Women

[21]

Fibrinogen

Plasma

254 to 284 mg/ml

372 to 419 mg/ml

Men

[21]

Fibrinogen

Plasma

303 to 331 mg/ml

381 to 415 mg/ml

Women

[21]

TNFα

Plasma

0.075±0.020 ng/ml

0.34±0.09 ng/ml

F344 Rat [120]

TNFa

Aorta

0.04±0.02U/mgDNA 0.13±0.02U/mg DNA

Organism Ref.

Rats

[121]

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(Table ) contd.....

Marker

Tissue

Young/Middle Age

Aged

Organism Ref.

TNFα mRNA

Coronary arteries

95±30

670±95

F344 Rat [122]

TNFα

Coronary arteries

100±10AU

300±30AU

F344 Rat [122]

TNFα

Muscle

2.5±0.9 pg/mg.Pr.

9.25±1.2pg/mg.Pr

F344xBN

[96]

TNFR1

Muscle

0.5±0.1AU

2.5±0.5AU

F344xBN

[96]

TNFα

Adipose

1.0 ± 0.1

1.7±0.1

Wistar Rat [24]

TNF-α

Liver

1.0 ± 0.2

2.4±0.3

Wistar Rat [24]

TNF-α

Brain Cortex

11.5±1.25 pg/mg

21.5±1.85 pg/mg

Wistar Rat [123]

TNF-α

Microglia

ND

917.2 ± 91.9 pg/ml

C57Bl6

[124]

IL-6

Plasma

36.8±3.6 U/ml

223.2±51.1 U/ml

Rats

[121]

IL-6

Plasma

62.5±30.5 pg/ml

180±65 pg/ml

SD rat

[125]

IL-6

Aorta

Rats

[121]

IL-6

Brain Striatum

9.75± 4.75 pg/mg

25.5±2.5 pg/mg

Wistar Rat [123]

IL-6

Brain Cortex

4.0±0.1 pg/mg

9.5±0.75 pg/mg

Wistar Rat [123]

IL-6

Cerebral Cortex

51.5±4.5 pg/mg

108±12 pg/mg

IL-6

Microglia

211.8±31.7pg/ml

3735±1000 pg/ml

C57BL/6 [124]

IL-1β

Plasma

64.01±11pg/ml

192±54.9pg/ml

Wistar Rat [24]

IL-1β

Liver

1.0 ± 0.1 AU

2.0±0.4 AU

Wistar Rat [24]

IL-1β

Hippocampus

0.30±0.02

0.40±0.10

IL-1β

Brain Striatum

12.5± 0.7 pg/mg

24.5±0.1 pg/mg

IL-1β ir

Neurons

5.67 ± 1.78

54.20 ±7.54

Rat

[127]

CRP

Plasma

8.25±0.55 ng/ml

11.5±0.25 ng/ml

C57Bl6

[128]

CRP

Plasma

0.98±0.08µg/mg.Pr.

2.85±0.15µg/mg.Pr.

2.3±2.3kU/mg.DNA 7.4±1.2kU/mg.DNA

BALB/c

Rat

[126]

[127]

Wistar Rat [123]

Fisher 344 [118]

More consistent data as to the aging-associated changes in pro-inflammatory mediators was provided through analyses of various tissues. Studies with peritoneal macrophages isolated from mice of different ages showed an agingassociated increase in the basal TNFα production, from 16.9±0.5 units/ml to 37.0 ±4.3 units/ml in males, and from 13.3±1.2 units/ml to 29.1±4.0 units/ml in females [5]. Elevated expression of TNFα has also been reported for aorta, muscle, adipose tissue, liver, and hypothalamus of aged rats (see Table 1), while IL-1β synthesis is found to increase in liver and brain tissues. This would suggest that aging-associated changes at the local, rather than systemic level are important for the onset of inflammaging.

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Molecular and Cellular Mechanisms for Aging-Associated Induction of Cytokine Production in the Absence of Infection The mechanisms behind the up-regulated production of pro-inflammatory mediators in the elderly are not well understood. According to the currently most prominent hypothesis, cells in the aging organisms acquire the so-called senescence associated secretory phenotype, or SASP, which is manifested by an increased secretion of pro-inflammatory molecules. It should be noted however, that while cellular senescence in vitro is a well-defined process, the relevance of senescent cells in vivo is less clear. Several mechanisms explaining the cause of SASP have been proposed: (i) DNA Damage [25]: DNA damage accumulates in the cell with age [26]. Persistent DNA damage leads to activation of the DNA damage sensors and triggers SASP. Until recently, little attention has been paid to the possibility that own damaged DNA can induce innate immune response. This was because damaged DNA resides in the nucleus, while the known censors that detect pathological DNA (typically foreign) and can launch immune response (as in the TLR receptor-mediated responses) are located in the cytoplasm or on the plasma membrane. It was found however, that the same nuclear DNA damage sensors and amplification loops that trigger the well-established DNA repair mechanisms, also can initiate “nuclear-to-cytoplasmic” signals and launch inflammatory responses. In the nucleus, depending on the type of DNA lesions, specific DNA damage sensors are responsible for the initial recognition of the DNA damage. For example, Mre11-Rad50-Nbs1 complex recognizes ds-breaks [27], UV- inflicted DNA lesions are recognized by XPC-RAD23-CETN2 complex [28], while MutS proteins and DNA glycosylases recognize mismatched and damaged bases. The initial damage recognition is followed by activation of two nuclear kinases, the ataxia telangiectasia mutated (ATM) and the ATM/Rad3 related (ATR) that serves to augment the signal [25] . While the main role of the ATM and ATR kinases is to induce DNA repair mechanisms, more recent studies have shown that they also activate Nuclear Factor κB (NFkB), interferon regulatory factor, or p38 activity in response to DNA damage and are required components of the pathways inducing SASP [29].

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(ii) Oxidative Stress: The “free radical theory of aging” postulates that agingassociated decay in the mitochondrial functions of various cells gradually leads to increased production of reactive oxygen species (ROS). Combined with a deterioration of the major anti-oxidant systems like GSH, these changes lead to the onset of a state of elevated oxidant stress in many, although not all tissues of the aged organism. The increased levels of ROS have been shown to chronically activate the redox-sensitive NFkB transcription factor, c-Jun N-Terminal Kinase (JNK), and other signaling molecules linked to the induction of mRNA transcription of major cytokines of the APR [4, 11, 30, 31]. NFkB was shown to be redox sensitive in the early 90’s, and many groups have studied the issue since then, providing strong evidence that indeed some parts of the NFkB pathway are redox sensitive [32]. At the same time however, they also showed that the redox sensitivity is not universal, but limited to some cells and not others, and it is strictly dose dependent [33]. While modest levels of oxidative stress could be stimulatory, excessive oxidative stress is possibly a negative modulator of NFkB activation. It has also become evident that in many cases, ROS serve only as coactivators that act in synergy with other classical inducers of NFkB, like LPS or TNFa. There is no comprehensive mechanism explaining the ROS-induced activation of NFkB. Both, the cytoplasmic and the nuclear component of the NFkB pathway have shown redox-sensitivity. According to the classical pathway of NFkB activation, in non-stimulated cells, cytoplasmic NFkB is sequestered by inhibitory proteins of the IkB family. The key players involved in the NFkB activation are IkB kinase α (IKKα) and IKKβ. The IKKα/ IKKβ heterodimer is associated with another regulatory subunit, IKKγ. Upon stimulation, the upstream protein tyrosine kinase is recruited to the IKKα/ IKKβ complex via IKKγ, and phosphorylates IKKβ. The so activated IKK complex then phosphorylates the inhibitory subunit IkB of NFkB/IkB to trigger its degradation via the 26S proteasome. Following dissociation from IkB, NFkB translocates to the nucleus, where it binds to the promoter region of relevant gene and drives its expression [34, 35]. Oxidants have been shown to activate upstream kinases, such as the MAPK family and NIK, modulating the activity of the IKK complex. Elevated IKK activity correlates with the degree of phosphorylation of residues in the activation loops of IKKα and IKKβ, as well as with the Cys-mediated dimerization of IKKγ. A redox-sensitive modulation of PP2A activity, which is

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inhibited by ROS, has also been shown to potentiate NIK and IKK phosphorylation. Direct oxidative modification of components of the IkB/NFkB complex has also been reported [36]. The confluence of these events leads to activation of the IKK complex and nuclear translocation of the active NFkB to the nucleus. In the nucleus, NFkB binding to DNA depends on the redox state, with sulfhydryl oxidizing agents inhibiting and reducing agents increasing DNA binding [37]. In some cells, ROS-induced production of thioredoxin has been found to affect the DNA binding activity of NFkB. Elevated NFkB activity during aging has been observed in the rat kidney [38], human skeletal muscle [39] and hypothalamus of mice [40]. Importantly, NFkB activation leads to the expression of pro-inflammatory intermediaries such as TNFα, IL-6, COX-2, and iNOS, which themselves are potent inducers of NFkB, thus creating an auto-activating loop [34]. In addition to NFkB, ROS-induced up-regulation of JNK-, AP-1-, and C/EBPdependent cellular responses has been linked to the onset of inflammaging [41]. As with NFkB, the exact mechanisms of oxidative stress-induced activation of these molecules are not quite clear, but ROS-induced dissociation of thioredoxin1 from ASK1 (the kinase upstream of JNK), is the plausible cause for JNK and AP-1 up-regulation with aging. (iii) Adipocyte De-Differentiation and Dysfunction: Another major cause of inflammaging is change in adipocyte functions. One of the primary roles of adipose tissue is to sequester excess fat away from the circulation and organs where free fatty acids could exert cytotoxic effects commonly referred to as lipotoxicity [17]. Adipocytes protect against lipotoxicity by storing the excess fatty acids in the form of triglycerides. Adipocytes are formed throughout one's life span from pre-adipocytes. However, the capacity of pre-adipocytes to differentiate has been shown to decrease with aging, leading to an increased abundance of small, insulin-resistant, dysfunctional adipocytes that fail to store as much fatty acids as adipocytes from younger animals. With aging, both preadipocytes and adipocytes become more susceptible to lipotoxicity and free fatty acids especially saturated ones like palmitic acid. These changes cause adipocytes to secrete pro-inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), TNFα, and IL-6 [42 - 44]. Furthermore, the aging-related

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impaired capacity of adipocytes to store lipids results in increased circulation of free fatty acids, leading to systemic inflammatory responses. Adipocyte dysfunction may thus lead to vicious cycles of propagated inflammation, since the induction of pro-inflammatory secretagogues by adipocytes leads to the activation of cells of the innate immune response. The resulting monocyte recruitment and macrophage activation in turn promotes the secretion of additional macrophagederived pro-inflammatory factors, increased release of fatty acids from adipocytes, and increased lipotoxicity. Although the adipose tissue is undisputedly a key player in aging-associated inflammation, the mechanisms behind aging-associated adipocyte dysfunction are not well defined. The decreased capacity of pre-adipocytes to differentiate with age seems to be at least partly due to reduced expression of key transcription factors, like C/EBPα, involved in adipogenesis [45]. (iv) Damaged Cell Components: The accumulation of damaged cellular components in the cells of the aging organisms has been known for a long time and has given the basis of the so called “garbage can” hypothesis of aging. Recently, it became clear that the “garbage” might contribute to inflammaging through a mechanism involving autophagy. Autophagy is an evolutionary conserved process that controls cellular homeostasis by facilitating the clearance of damaged cellular components trough degradation in the lysosomes [46]. It has been observed that deficiency in autophagy could stimulate inflammatory signaling in sensitive tissues by inducing DDR and inflammasome formation. Consequently, autophagy has been proposed to play a key role in suppressing inflammation by eliminating potential endogenous stressors [47]. During the last decade, several studies reported that macroautophagy (the major type of autophagy responsible for segregating organelles for lysosomal degradation) as well as chaperon-mediated autophagy (responsible for the selective degradation of cytosolic proteins) decline with aging. As a result of the decline, aging cells accumulate damaged proteins as well as organelles, specifically dysfunctional mitochondria that in turn fuel oxidative stress by producing excess ROS [48 - 50]. Changes in lysosome functions underlie the aging-associated decline in autophagy. An accumulation of lipofuscin in the lysosomes is seemingly responsible for the defects in macroautophagy, while and age-related decrease in

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the expression of LAMP-2A, a lysosomal receptor protein, is implicated in the decline of chaperon-mediated autophagy. Notably, increasing the autophagic capacity of the cells by pharmacological or genetic manipulations can prevent the pathology linked to the aging process and even extend lifespan [51, 52]. Aging-Associated Changes in the Homeostasis of Bioactive Lipid Metabolites Bioactive lipid metabolites are class of lipid molecules whose levels are very low in a normal, healthy state. In response to a wide range of cellular stressors, most notably inflammation, the production of bioactive lipids is transiently stimulated. TNFα and IL-1β signaling pathways all involve the activation of a lipid metabolizing enzyme(s) with the resulting generation of bioactive metabolite(s) either at the plasma membrane or in intracellular organelles, which mediate down-stream signaling. Some less hydrophobic lipid metabolites can also be released into the circulation and play the role of paracrine and endocrine signals by activating specific G protein-coupled receptors. Sphingolipids (in particular, ceramide and sphingosine-1-phosphate), and the eicosanoids (prostaglandins and leukotrienes) are the major bioactive lipid metabolites that participate in the regulation and propagation of cellular response to inflammation. Interestingly, aging is correlated with dysregulation of the overall lipid metabolism and shift in the basal steady-state levels of several key bioactive lipid metabolites, favoring the onset of a pro-inflammatory state. Ceramide has been extensively studied for its role as a cellular sensor to stress. TNFα, IL-1β, Fas ligand, and oxidative stress are just a few of the agents that are shown to trigger generation of ceramide through distinct metabolic pathways. The resulting increases in ceramide can initiate or modulate cellular responses by activating pro-apoptotic pathways or activating pro-inflammatory second messengers, including JNK and NFkB. Ceramide directly interacts with and regulate phosphatases from the PP2A family [53], PKCζ, and Ceramide-activated Protein Kinase. Ceramide is required for the activation of JNK [54 - 56] and NFkB [57, 58] in response to several cytokines. Mounting evidence however suggests that in the course of aging, the roles of ceramide as mediator of host response to infection and stress change. Studies in the late 80’s and early 90’s found increased basal levels of ceramide during aging in a variety of cells,

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including hepatocytes [59 - 61]. Studies in cellular models of senescence using human diploid fibroblast related these increases to retardation in the rate of cell growth via inhibition of rB hyper-phosphorylation and the appearance of markers of senescence, such as β-galactosidase [62, 63], suggesting a fundamental role for ceramide in the mechanisms leading to cellular aging. In rodents, ceramide concentrations also change following a “development-aging” continuum: normal aging is associated with accumulation of ceramide, while caloric restriction (CR) that extends the rat life span has been found to decrease the levels of ceramide [64]. Aging-associated changes in the basal levels of ceramide have been well documented in liver [60, 65], T-cells [66], adipocytes [43], muscle [39] and in the brain [67]. Mass-spectrometry-based analyses had revealed that in some cases, only specific sub-species of ceramides are affected. In muscle and in T-cells for example, only C16:0 ceramide is increased [39], while C24:1 and C16 are affected in the liver [65]. An ongoing research effort had provided ample evidence that the fatty acid make-up of ceramides determines their biological effectiveness, suggesting differential roles of C16:0, C18:0 and C24:1 ceramides in cellular stress response and underlying the need of structure-cognizant analysis of ceramides. The mechanisms of aging-associated accumulation of ceramide seem to involve chronic up-regulation of neutral sphingomyelinase activity [60, 68], specifically, neutral sphingomyelinase-2 (the product of the smpd3 gene), which at least for hepatocytes is likely attributed to increased oxidative stress [69]. These aging-associated changes seems to contribute to the onset of inflammaging by modulating signaling cascades of some pro-inflammatory cytokines, discussed later in this chapter. Another class of bioactive lipids that may contribute to inflammaging are the eicosanoids, comprising of both prostaglandins and leukotrienes that are products of arachidonic acid metabolism and have potent pro-inflammatory characteristics [70]. The rate-limiting enzyme for the conversion of arachidonic acid to eicosanoids is cyclooxygenase (COX). The levels of COX-2 mRNA and protein increase with age [38, 71, 72]. In macrophages, COX-2 up-regulation has been attributed to increases in ceramide and NF-kB activation in the aged animals. Consequently, macrophages and spleen cells from old mice and peripheral blood mononuclear cells from elderly human subjects synthesize significantly more

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prostaglandin E2 (PGE2) than their young counterparts [73]. The aging-associated increases in PGE2 production has been implicated in the declined T cells functions in elderly. The expression of both forms of COX, COX-1 and COX-2 is elevated in the aorta of old rats as compared to young counterparts, leading to elevated production of prostacyclin and thromboxane and impaired vasorelaxation [74]. Dys-balanced production of several prostaglandins in the kidney of aged rats has also been documented and linked to aging-associated deregulation of glomerular filtration rate and other related kidney functions [75]. THE CONCEPT OF CELLULAR HYPERRESPONSIVENESS TO PROINFLAMMATORY AGONISTS Once established, chronic inflammation gains momentum due to amplification and feedback loops. A hyperresponsiveness to various inflammatory challenges has been observed in aged animals and humans and serves to propagate and amplify even small, subclinical increases in inflammatory cytokine levels. The classical illustration of aging-associated hyperresponsiveness comes from experiments with TLR-4-dependent responses. The administration of bacterial endotoxin, LPS, to mice or rats, results in a much more prolonged response in old animals as compared to young ones, as judged by the plasma levels of TNFα, IL1β, IL-12, PGE2, TXA2, PGH2 and PGG2 [76]. Following LPS injection, brain homogenates from old mice exhibited significantly higher levels of TNFα as compared to young ones (175±90 pg/ml versus 525±140 pg/ml) [18]. Aged animals also exhibit an exaggerated response to other cellular stressors, for example beta-amyloid peptide, resulting in higher induction of IL-1β in hippocampus [77] or to oxidants. Recent studies have given indications to the fact that such hyperresponsiveness occurs also in vitro, suggesting that in many, but not all cell types, various signaling pathways are affected by aging [6, 9, 13, 14, 78]. For example, when treated with LPS, TNFα, or pharmacological inducers of oxidative stress, peritoneal macrophages [6, 9], hepatocytes [13], and glial cells isolated from aged animals exhibit more severe and prolonged responses as compared to cells isolated from young animals. This is evidenced by substantial differences in the magnitude and temporal pattern of activation of COX-2 [6], JNK [14, 78], NF-κB

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[6], and C/EBP [13]. These studies had provided the basis of the hypothesis that onset of pro-inflammatory state in aging is due not solely to increased production of systemic factors by the senescent cells, but also to changes in cellular responsiveness. Importantly, concentrations of systemic pro-inflammatory mediators that are too low to appreciably affect response in young animals are capable of inducing significant signaling in aged ones. The causes of these agingassociated hyperresponsiveness are not entirely understood, but seemingly involve a decreased capacity of anti-oxidant defense, up- or down-regulation of proteins functioning as rate-limiting factors in signaling cascades, and disruption of the balance between kinase and phosphatase activities. It has to be noted that the increased cellular responsiveness to pro-inflammatory stressors is in sharp contrast to the effects aging has on the cellular response evoked by growth factors like PDGF, EGF-1, and even insulin and IGF1. If anything, the signaling pathways activated by these growth factors are down regulated with age, bringing about the decreased proliferative and regenerative capacity that is characteristic of the cells of the aged. Mechanisms of Cellular Hyperresponsiveness: The hepatic IL-1 β signaling pathway as an example of aging-associate hyperresponsiveness due to intrinsic cell-autonomous changes in signaling pathways. The basal systemic levels of IL-1β increase with age only modestly [79], and yet, various IL-1β-related functions, like the regulation of acute phase protein (APP) expression in liver experienced significant age-dependent alterations [80, 81] suggesting that changes in cellular signaling pathways might be involved. Cellular responses to IL-1β are mediated through the interleukin-1 receptor type I (IL1RI). Ligand binding results in the recruitment of several adaptor proteins [82] and activation of the IL-1R-associated kinase-1 (IRAK-1). IRAK-1 phosphorylation leads to K48- or K63-dependent ubiquitination of the kinase and respectively, to either proteasomal degradation or to interaction with NEMO1 followed by NFkB activation. Importantly, the proteasome-mediated degradation of IRAK-1 results in the termination of the signaling cascade [83]. The rate of IRAK-1 degradation is important determinant of the magnitude of the cellular response to IL-1β (as well as to LPS which signals via similar pathway) [84 - 86].

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Several studies have shown that the IL-1β signaling cascade in the liver is strongly affected by aging [69, 78, 87]. The possibility to isolate primary hepatocytes from rats of different ages that retain many aging-associated differences in vitro has helped to elucidate in details the molecular mechanisms for the altered response. It has been shown that the basal expression levels of IL1RI, IRAK-1, TAK-1 and JNK remain unchanged during aging; yet, stimulation with IL-1β evokes a more potent JNK phosphorylation in primary hepatocytes isolated from aged rats than in hepatocytes isolated from young ones [78]. The increased phosphorylation of JNK leads to increased phosphorylation of c-jun and more potent stimulation of the expression of Insulin-Like Growth Factor Binding Protein 1 (IGFBP1) [87]. Recent studies into the mechanisms underlying aging-associated hyperresponsiveness to IL-1β in liver have revealed that increased state of oxidative stress and chronic up-regulation of oxidative stresssensitive neutral sphingomyelinase-2 (NSMase-2) in aged animals are implicated. The neutral sphingomyelinase-2 (nSMase-2) belongs to a family of 5 enzymes which all hydrolyze Sphingomyelin (SM) to ceramide [41]. Pro-inflammatory cytokines like IL-1β and TNFα transiently activate nSMase-2 causing transient elevation in the concentration of cellular ceramide. In young animals, the IL-1-induced activation of NSMase2 serves to regulates the extent of IRAK-1 phosphorylation and subsequent K48-ubiquitination and proteasomal degradation in a PP2A-dependent manner [88]. During aging however, the constitutive increases in nSMase-2 activity [59, 60] lead to delayed IRAK-1 phosphorylation, ubiquitination and degradation, increased abundance of IRAK-1 and re-activation. Notably, suppression of nSMase-2 in hepatocytes from aged animals, either by siRNA silencing or by pharmacological inhibitors, reduces nSMase activity to levels similar to those found in young animals [78] and restores normal response to IL-1β, evidenced by a “youthful” pattern of IRAK-1 degradation, JNK and cjun activation and attenuation of the hyperactive physiological responses like acute phase protein secretion. Recent evidence indicate that the age-associated changes in nSMase-2 activity are due to a decline in hepatic GSH content, providing a link between oxidative stress and IL-1β hyperresponsiveness. NSMase-2 is also a key mediator in the TNFα signaling cascade [89 - 91] and has been linked to endothelial nitric oxide synthase activation [92], vascular cell

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adhesion molecule (VCAM) and intracellular adhesion molecule 1 (ICAM) induction [91], all of which have prominent roles in vascular inflammatory responses. Notwithstanding, muscle precursor cells isolated from 32-month-old animals, that are key therapeutic target for improving age-related skeletal muscle loss, exhibit an increased NF-kB activation in response to TNFα, compared to the same cells isolated from 3-month-old animals. An elevated TNFα-induced activation of AP-1 and ERK has been observed in aortic vascular smooth muscle cells from old versus young rats. The mechanisms of aging-associated TNFα hyperresponsiveness have not been investigated; however, the possibility that differences in the basal levels of TNFα receptor, NFkB, AP-1, or ERK are responsible for the augmented response has been ruled out. Therefore, agingassociated hyperresponsiveness is not limited to the IL-1β signaling cascade and might be a common feature of other cytokine signaling pathways. DIETARY AND PHARMACOLOGICAL INTERVENTIONS THAT SUPPRESS AGING-ASSOCIATED RISE IN INFLAMMATORY MARKERS In their original paper on inflammaging, Franceschi at al. postulated that the persistence of inflammation over time represents only the “biologic background (first hit) favoring the susceptibility to age-related diseases” and that a “second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes” [4]. Consequently, one can hypothesize that if indeed inflammaging is a fundamental biological basis of aging, then its suppression should extend life span. Some support to that hypothesis comes from studies with extremely old mice (corresponding to centenarians in humans). While the increased basal levels of proinflammatory cytokines are seen in the old and very old animals, the extreme long-lived mice seem to maintain an overall profile of IL-6, IL-1β, and TNFα that is similar to middle-aged mice [93]. Furthermore, mice expressing a constitutively active IKKβ that stimulated NF-κB activity in the hypothalamus show a reduction in longevity, whereas expression of dominantnegative IκBα, which inhibits NFκB, prolongs their lifespan [40]. Studies with non-genetic animal models of delayed aging provide further correlations between

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inflammaging and longevity. These experiments consistently show that extending life span in animals is correlated with subdued sterile inflammation. In many cases the mechanisms are known (at least to some extent) and point to manipulations of the very causes of inflammaging discussed earlier. Caloric Restriction Life expectancy is profoundly affected by caloric intake. In many organisms, including yeast, worms, flies, rodents, and monkeys, caloric restriction (CR) is the most robust non-genetic approach to extend mean as well as maximal lifespan [94, 95]. Reduction of the overall energy intake by 30-60% from the intake of ad libitum fed animals (typically starting after the animals reach maturation) extends lifespan by 20 to 40%, making CR a promising model to understand and possibly control the aging process. In many studies, CR has been shown to subdue the state of chronic inflammation. In the rat for example, CR has been found to reduce agedependent loss in muscle mass concomitant to the elimination of aging-associate elevation in local TNFα production [96]. The aging-associated elevation of IL-1β, IL-6, and TNFα in the plasma, adipose tissue, liver, muscle and hypothalamus is also significantly diminished, especially in adipose and liver tissues, by moderate caloric restriction [24]. Another inflammatory biomarker, CRP, whose plasma levels increase 2-3 fold in the course of aging is similarly affected by CR so that the plasma CRP levels in old CR rats remain close to the levels typically seen in young animals. Studies from our laboratory with hepatocytes from calorie restricted aged rats have shown that CR significantly subdues the hyperresponsiveness to IL-1β. Hepatocytes isolated from 20-month old rats kept at 30% CR throughout their lifetime have ceramide levels and nSMase-2 activity similar to those seen in hepatocytes from young animals. More importantly, the IL-1-induced hyper-activation of JNK and IGFBP1, typically seen in hepatocytes of old rats, is absent in hepatocytes from old CR rats. CR also inhibits the aginginduced chronic activation of NSMase and reduces ceramide content in the hippocampus and brain cortex of the rat [97]. The correlations between increased life span and the alleviation of inflammatory markers seen during CR seem to support the notion that inflammaging is a basic characteristic of the aging process. One interesting, yet unresolved issue with the

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interpretation of the results discussed above is related to the fact that animals maintained on CR are very lean throughout their life and have no adipose tissue. Having in mind that changes in fat tissue and excessive lipotoxicity is one of the main sources of inflammation during aging, the alleviation of inflammaging seen in old CR animals could be explained by the overall leanness of the animals. Such interpretation opens the possibility that the extension of life span is not necessarily linked to caloric intake but to the lack of adipose tissue (and respectively inflammaging). Studies with mice lacking the insulin receptor specifically in adipose tissue (FIRKO mice) lend support to that hypothesis. The FIRKO mice have reduced fat mass, are protected against age-related obesity and although their food intake is normal, they live longer than wild type counterparts [98]. Other studies however indicate that this might not be the case. More specifically, the ob/ob mice (that are one of the most studied genetic model of obesity) experience the same life extension benefit when placed on CR as do lean mice, in spite that they remain obese [99]. Alternatively, a decrease in oxidative stress, and respectively oxidative damage, due to slower metabolic rate could be another mechanism for the reduced inflammaging during CR. Other Dietary Approaches that Attenuate Inflammaging The polyphenol resveratrol, found mainly in grapes and in red wine is known to protect against oxidative stress, inflammation, and cancer and is believed to be a mimetic of caloric restriction in terms of longevity [100]. Many studies have indicated that dietary supplementation of resveratrol attenuates inflammaging. For example, the exacerbated LPS-induced increases in the plasma IL-1β levels and the hippocampal IL-1β mRNA expression in aged mice are reduced by resveratrol. The effects correlate with improved behavioral and memory functions [101]. The aging-associated increase in spleenocyte TNF-α and INF-γ production is also decreased by resveratrol intake [102]. Treatment of aged vascular smooth muscle cells with resveratrol in vitro has significant anti-inflammatory effects, reversing aging-induced cytokine secretion by inhibiting NFkB activation, attenuating mitochondrial superoxide production, and upregulating the transcriptional activity of Nrf2 [103]. The main targets of resveratrol are the energy-sensing AMP-activated kinase (AMPK) that regulates cellular metabolism and the silent information regulator 2 (Sir2) family of proteins (sirtuins or SIRTs),

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which belong to class III histone/protein deacetylases and are implicated in CRinduced life extension via the inhibition of the mTOR and NFκB pathways [104]. Resveratrol however might have multiple additional targets including the COX, the PI3 and p70S6 Kinases, as well as the estrogen receptor. While the beneficial effects of resveratrol on longevity seem to be well documented in animals, the evidence in humans is not sufficient. In fact, some human studies (with rather small cohorts) have indicated that resveratrol may have, at least at cellular levels some pro-inflammatory properties [105]. Alternative ways to diminish age-related inflammation include the inclusion of some micronutrients (zinc supplement) [106] or anti-inflammatory products of the eicosanoids. Docosahexaenoic acid (DHA), for example significantly reduces IL6 secretion old 3T3-L1 adipocytes [107]. A new family of eicosapentaenoic acid and DHA-derived lipid mediators called resolvins [108], have shown effective anti-inflammatory properties, suggesting that incorporating fish oils may be an option for containing age-related rise in inflammatory markers. The consumption of plant sterols and stanols along with omega-3 fatty acid has also been found to reduce CRP, TNF-α, and IL-6 in humans [109, 110]. Exercise Apart from dietary intervention, regular moderate physical exercise had emerged as an alternative approach to counter age-dependent increases in inflammatory biomarkers. Several studies in older individuals (average age> 60 years) have found an inverse relation between physical activity and inflammatory markers [108, 111 - 116]. A randomized clinical study with sedentary aged population (> 64 years) that underwent a moderate physical activity for 10 months showed that the levels of CRP, IL-6 and IL-8 decreased significantly compared to the control group [117]. Studies in rats have shown an additive effect of lifelong exercise and CR in alleviating aging-associated increases in plasma CRP [118]. In mice, exercise training was more effective than resveratrol in alleviating inflammatory markers but no additive effect was observed [119]. CONCLUDING REMARKS Contemporary science had made gigantic strides towards understanding the basic

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biology of aging. The ongoing research on inflammaging had illuminated important new principles that govern the process. For one, the mechanisms responsible for the onset of inflammaging that has been identified so far, point to the fact that systems that have evolved to be beneficial and protective in young individuals, had been turned into a platform for the development of multiple aging-associated diseases. DNA repair mechanisms that protect the genome, the ability to sequester lipotoxic fat in adipose tissue, or to clear damaged organelles and molecules at cellular level, all serve to protect the organism and ensure survival. These functions all gradually decline in the elderly, but apparently aging, aging-associated diseases, and eventually death are not simply the result of the lack of protection. Instead, another defense system that had evolved to ensure survival of the host amidst harmful environmental pathogens, the innate immune response, plays a more fundamental role. The chronic low-grade up-regulation of key components of the innate immune response has emerged as a convergence point, where the consequences of the many dysfunctions of the aging cell culminate. Second, it has also become apparent that distinct molecular mechanisms cause inflammaging. Notably, significant portions of these mechanisms are already known as they include parts of fundamental cellular functions, like DNA repair, autophagy, and others. Understanding the connection between these basic functions and the stimulation of innate immune response seems to be an achievable task. Finally, it is also apparent that viscous cycles propagate and amplify initially small responses. These cycles play a key role in the establishment of inflammaging to a level sufficient to cause tissue degeneration and eventually organismal death. Understanding and controlling these cycles seems to be more challenging but still possible. “All diseases run into one, old age” Ralph Waldo Emerson

CONFLICT OF INTEREST The authors confirm that authors have no conflict of interest to declare for this publication.

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[120] Csiszar A, Labinskyy N, Smith K, Rivera A, Orosz Z, Ungvari Z. Vasculoprotective effects of antitumor necrosis factor-alpha treatment in aging. Am J Pathol 2007; 170(1): 388-98. [http://dx.doi.org/10.2353/ajpath.2007.060708] [PMID: 17200210] [121] Belmin J, Bernard C, Corman B, Merval R, Esposito B, Tedgui A. Increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats. Am J Physiol 1995; 268(6 Pt 2): H228893. [PMID: 7611479] [122] Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G. Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries. FASEB J 2003; 17(9): 1183-5. [PMID: 12709402] [123] Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B. Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 2009; 87(11): 2484-97. [http://dx.doi.org/10.1002/jnr.22074] [PMID: 19326443] [124] Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 2012; 33(1): 195. e1-12 [125] Xin DL, Harris MY, Wade CK, Amin M, Barr AE, Barbe MF. Aging enhances serum cytokine response but not task-induced grip strength declines in a rat model of work-related musculoskeletal disorders. BMC Musculoskelet Disord 2011; 12: 63. [http://dx.doi.org/10.1186/1471-2474-12-63] [PMID: 21447183] [126] Ye SM, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol 1999; 93(1-2): 139-48. [http://dx.doi.org/10.1016/S0165-5728(98)00217-3] [PMID: 10378877] [127] Badowska-Szalewska E, Ludkiewicz B, Sidor-Kaczmarek J, et al. Hippocampal interleukin-1beta in the juvenile and middle-aged rat: response to chronic forced swim or high-light open-field stress stimulation. Acta Neurobiol Exp (Warsz) 2013; 73(3): 364-78. [PMID: 24129485] [128] Yamato M, Ishimatsu A, Yamanaka Y, Mine T, Yamada K. Tempol intake improves inflammatory status in aged mice. J Clin Biochem Nutr 2014; 55(1): 11-4. [http://dx.doi.org/10.3164/jcbn.14-4] [PMID: 25120275]

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CHAPTER 7

Allergic Inflammation Joshua L. Kennedy*, Matthew C. Bell Departments of Internal Medicine and Pediatrics, Division of Allergy and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Abstract: Atopic diseases, including seasonal and perennial allergic rhinitis, asthma, atopic dermatitis, and food allergy, affect a significant proportion of the United States population. Specific host inflammatory patterns characterize these allergic responses. Whether the innate or adaptive immune responses are recruited for a specific antigen, the signature of cytokines secreted will identify this inflammatory pattern and, in the presence of the correct cellular infiltrate, will yield enhanced T helper 2 (Th2), or allergic, inflammation. A description of the various cell types involved in allergic inflammation and the inflammatory responses leading to allergy, including innate and adaptive immunity, are presented in this chapter. Specific pharmacologic modulation utilizing monoclonal antibodies is also discussed.

Keywords: Adaptive Immunity, Allergic Inflammation, Cytokines and Allergy, Pharmacologic Modulation, Th2 inflammation. INTRODUCTION Allergic diseases, including allergic rhinitis (seasonal and perennial), asthma, atopic dermatitis, and food allergy, affect approximately 1 in 5 adults in the United States [1]. In sensitized individuals, exposure to specific allergens (antigens) leads to symptoms of runny nose, sneezing, itchy eyes, cough, itchy skin, and rash, and, in some patients, more severe symptoms, including anaphylaxis. Anaphylaxis is defined as a severe allergic reaction with acute onset involving two or more body systems. These symptoms can include respiratory Address correspondence to Joshua L. Kennedy: University of Arkansas for Medical Sciences, 13 Children’s Way, Slot 512-13, Little Rock, AR 72202, USA; Tel: 501-364-1060; Fax: 501-686-8765; Email: [email protected]

*

Robert F. Diegelmann & Charles E. Chalfant (Eds.) All rights reserved-© 2016 Bentham Science Publishers

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compromise, wheezing, reduced blood pressure (hypotension), involvement of the skin (urticaria or hives), swelling (angioedema), persistent gastrointestinal symptoms (abdominal pain, vomiting, and diarrhea) after exposure to an allergen that may progress to death if not treated quickly and appropriately with intramuscular epinephrine [2]. A distinct inflammatory pattern can be delineated in atopic, or allergic, individuals based upon characteristic cytokine profiles and cellular infiltrates. Cytokines are secreted proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses, subsequently leading to inflammation [3]. Distinct antigens (allergen)-specific cytokine profiles within a given individual polarize the inflammatory environment and, in atopic subjects, promote “pro-allergic” responses. In allergic individuals, a combination of innate and adaptive immune signals produces a distinctive cytokine milieu, enhancing a predominant T helper type 2 (TH2) response and production of the allergic antibody, IgE. Because cytokines serve as critical mediators of the immune response, they are attractive targets for therapeutic intervention in a variety of allergic disorders. For this chapter, distinct cell types involved in generating and maintaining allergic inflammation will be discussed. In addition, cytokines leading to TH2 immune responses and IgE production are categorized as those predominantly associated with innate and adaptive immune responses (Table 1). CELLS INVOLVED IN ALLERGIC INFLAMMATION Allergic inflammation begins with the exposure of an allergen at the epithelial cell surface of the nose, lung, gastrointestinal mucosa, and/or skin, triggering a cascade of inflammatory signals. First, through stimulation of various receptors on the surface of the epithelial cells, innate cytokines are secreted that may bias toward a TH2 response (see section Innate Cytokines Involved in Allergic Inflammation) [4 - 6]. Second, dendritic cells (DCs), which function as professional antigen presenting cells (APCs), will capture the allergen and travel to regional lymph nodes. The allergen is subsequently presented to naïve T cells within the lymph node through major histocompatibility complex (MHC) class II receptors (Signal 1). Signal 2 is a verification step, which requires the interaction

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of CD80/86 on the surface of DCs to CD28 on T cells. If this step does not occur, the T cell presumes that it is recognizing self-antigen and becomes anergic, or turns off. Table 1. Summary of Innate and Adaptive Cytokines their receptors and targets. Allergic Cytokine Chromosome Receptor Inflammation (Human)

Sources

Targets

TSLPR/ IL7R-chain

Epithelial cells Fibroblasts

Dendritic cells: increased ability to attract TH2 cells Eosinophils: Induced release of proinflammatory cytokines and chemokines Mast: Cells: Increased production of TH2cytokines T Cells: Increased differentiation to TH2 cells Basophils: Increased production of TH2 cytokines and increased responsiveness to IL-33

IL-25 Chr 14 (IL-17E)

IL17R

Epithelial cells Fibroblasts Eosinophils Mast Cells

T cells: Increased differentiation to TH2 cells Basophils: Increased production of TH2 cytokines Mast cells: Increased production of TH2 cytokines ILC2: Release of IL-5 and IL-13

IL-33

IL1RL1 (ST2)

Epithelial cells Smooth muscle cells Keratinocytes Dendritic cells Macrophages

T cells: Increased differentiation to TH2 cells Macrophages: increased cytokine production Dendritic cells: Increased cytokine production, up regulation of MHC and co-stimulatory molecules Eosinophils: Increased proliferation, survival, and chemokine production Basophils: Increased production of TH2 cytokines Mast cells: Increased production of TH2 cytokines ILC2: Release of IL-5 and IL-13

Innate cytokines TSLP

Chr 5

Chr 9

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(Table ) contd.....

Allergic Cytokine Chromosome Receptor Inflammation (Human)

Sources

Targets

Adaptive cytokines IL-3

Chr 5

IL-3R (CD123)/ common beta chain (CD131)

T cells Basophils Mast Cells

Hematopoietic stem cells: Increased production of mast cells, basophils, neutrophils, eosinophils, macrophages, erythrocytes, megakaryocytes, and dendritic cells Eosinophils: Increased degranulation Mast Cells: Increased survival and histamine release Basophils: Increased survival and IL-4, IL-6, and histamine release

IL-4

Chr 5

IL-4R/ common gamma chain (CD132)

T cells Basophils Mast cells Eosinophils

Airway smooth muscle cells: Increased airway hyperresponsiveness Basophils: Increased recruitment Eosinophils: Increased recruitment Mast cells: Increased recruitment Macrophages: Increased T TH2 phenotype- alternative macrophage T cells: Increased recruitment, increased TH2 differentiation, increased production of TH2 cytokines B cells: class switch to IgE

IL-5

Chr 5

IL-5R (CD125)/ common beta chain (CD131)

T cells Eosinophils Mast cells

Eosinophils: Increased proliferation, chemoattraction, maturation, functional activation, and degranulation Basophils: Increased proliferation, maturation, and functional activation

IL-9

Chr 5

IL9R (CD129)/ common gamma chain (CD132)

T cells

Mast cells: Increased recruitment, maturation, increased expression of proteases, up regulation of IgE receptor T Cells: Increased growth and proliferation

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(Table ) contd.....

Allergic Cytokine Chromosome Receptor Inflammation (Human) IL-13

Chr 5

GM-CSF Chr 5

Sources

Targets

IL-13R1/ IL-4R

Mast cells Eosinophils Basophils T cells

Airway epithelial cells: Increased permeability, increased mucus production Airway smooth muscle cells: Increased airway hyper-reactivity Eosinophils: Promotes migration and survival Macrophages: Activation and enhanced MHC class II expression B cells: Class switch to IgE

GM-CSFR (CD116) / common beta chain (CD131)

T cells Airway epithelial cells Macrophages

Dendritic cells: Maturation Eosinophils: Increased survival, degranulation Macrophages: Differentiation, increased survival, increased cytokine production

TSLP= thymic stromal lymphopoietin; IL= interleukin; GM-CSF= Granulocyte Macrophage- Colony Stimulating Factor; Chr= chromosome; R= Receptor; CD= Cluster of differentiation; ILC2= Innate lymphoid cells, type 2.

Further, depending on the cytokine milieu present (Signal 3), the naïve T cell will differentiate into TH1 or TH2. In the presence of interleukin (IL)-4 or IL-13, the T cell will become a TH2 cell, subsequently secreting its own IL-4, IL-5, IL-9, and IL-13, amongst others. When the T cell interacts with a B cell, this cytokine milieu will cause the B cell to begin producing IgE to the specific antigen seen at the mucosal surface (Fig. 1) [6]. IgE then binds to receptors on the surface of allergic effector cells such as mast cells and basophils during what can be characterized as the sensitization stage. When the atopic individual is exposed to the allergen for a second time, activation and degranulation of mast cells and basophil occurs with release of mediators that cause tissue specific allergic responses (e.g. nasal congestion, cough, wheezing, vomiting) depending upon the site of exposure (Anaphylaxis Stage) (Fig. 2) [7]. Allergic inflammation requires the concerted effort of cells involved early in the immune response (so-called innate cells), such as epithelial cells, DCs, mast cells, and innate lymphoid type 2 cells, to generate antigen or allergen-specific immune responses along with recruitment of cells involved in maintaining this immune

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response (adaptive immunity), such as T cells, B cells, basophils, and eosinophils. In this section, we will discuss the roles of a few of these cell types important in allergic inflammation. Lymph Node CD40L

Mucosal Surface

CD40

T cell receptor

MHC Class II

CD4

Allergen (Antigen)

IL-25, IL-33, TSLP, etc.

Activation of the B cell with class switch to lgE

T

B

DC

lgE

IL-4, IL-13, etc.

Activation of Th2 cell MHC Class II

Signal 1: Recognition

CD80/86

T cell receptor

Signal 3: Cytokine Milieu

CD28

Signal 2: Verification

Fig. (1). Antigen/Host Interaction and Inflammation. See text for details. DC= Dendritic cell; T= T cell; B= B cell; IL= Interleukin; CD=Cluster of differentiation; L= Ligand; MHC= Major Histocompatibility Complex.

T Lymphocytes T lymphocytes are generally thought to maintain cellular immunity by recognizing specific epitopes, or markers, on foreign antigens. There are three categories of T cells: Helper T lymphocytes (CD4+), cytolytic T lymphocytes (CD8+), and T regulatory cells, or TREGS (CD4+CD25HIFoxP3+). Cytolytic T cells are typically involved in killing virally infected cells and tumor cells. T regulatory cells, as their name implies, are necessary to regulate and dampen specific actions involved in immunity [8]. We will spend the rest of this section discussing T

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helper cells (CD4+), specifically the T helper type 2 (TH2) cell.

SENSITIZATION STAGE 1

Antigen (allergen) exposure

2

Plasma cells produce lgE antibodies against the allergen

3

lgE antibodies attach to mast cells and basophils

ANAPHYLAXIS STAGE 4

Re-exposure to allergen

5

Allergen combines with IgE attached to mast cells and basophils, which leads to degranulation and release of histamine and other chemical mediators

Granules containing histamine, tryptase, and other mediators

Histamine, tryptase and other mediators released from mast cells and basophils

Fig. (2). IgE mediated allergic reactions. See text for details. *Reproduced with permission from the Journal of the Arkansas Medical Society [9].

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Human CD4+ T helper cells can be categorized into distinct effector subsets based on their cytokine repertoire [9]. This area of T cell biology is becoming more complex as distinct subsets continue to be identified [10], but the most simplistic view recognizes two main groups of T helper cells: type 1 and type 2. These subtypes play an important role in the overall health of the host, but each differs broadly in its mechanism of induction and the types of cytokines produced during pathogen elimination. Type 1 immune responses are induced in response to bacteria, viruses, fungi, and protozoa, and the predominant cytokine secreted by these cells is interferon [11]. In contrast to type 1 responses, TH2 cells are important in controlling infections with parasites and mediating allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis [12] through secretion of characteristic cytokines, including IL-4, IL-5, IL-9, and IL-13. These cytokines are important in “helping” the B cell class switch to the allergic antibody, IgE, ultimately generating the specific phenotype and symptoms associated with allergic conditions [13, 14]. B Lymphocytes B lymphocytes are responsible for antibody production, so called humoral immunity, and are typically recognized by the presence of specific receptors (CD19+ and CD20+) [15]. In the presence of IL-4 and IL-13 and with stimulation by TH2 cells that have recognized a specific allergen epitope, B cells will produce IgE. IgE is a monomeric immunoglobulin made of 4 heavy chain regions attached to a light chain. It has a very short half-life of only 2 days, and it is important in most allergic reactions. This antibody will bind to the high-affinity receptor (FcεRI) on the surface of mast cells and basophils leading to degranulation of these cells and typical allergic symptoms as well as anaphylaxis (Fig. 2) [16 - 18]. Eosinophils Eosinophils are implicated in the pathogenesis of numerous inflammatory processes, including parasitic helminth infections and allergic diseases [19 - 21]. Through numerous stimuli, the eosinophil will respond with secretion of cytotoxic granules containing eosinophil peroxidase, major basic protein, eosinophil

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cationic protein, and eosinophil-derived neurotoxin [22]. They are also an important source of TH2 cytokines, including IL-4, IL-5, IL-13, as well as many others [23 - 25]. In the human, IL-5 is the only known eosinophil hematopoietin [26]. This cytokine and its effects will be discussed in detail below. Basophils Basophils are the most rare of granulocytes, accounting for