Neuroinflammation New Insights into Beneficial and Detrimental Functions Neuroinflammation New Insights into Beneficial and Detrimental Functions Edited by SAMUEL DAVID, PhD Copyright © 2015 by Wiley-Blackwell. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. 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Central Nervous System Diseases–immunology. 2. Central Nervous System Diseases–physiopathology. 3. Autoimmune Diseases–physiopathology. 4. Inflammation–physiopathology. 5. Neurodegenerative Diseases–physiopathology. WL 301] RC346.5 616.8′0479–dc23 2014047521 Cover images: Headache © Ingram_Publishing/iStockphoto 10987654321 Contents Contributors xi Preface xvii PART I Introduction 1 1 Immune Response in the Human Central Nervous System in Multiple Sclerosis and Stroke 3 Hans Lassmann Introduction 3 The Concept of Neuroinflammation 3 Basic Principles of Immune Surveillance and Inflammation by Adaptive Immune Responses 4 Inflammation in the Central Nervous System of Patients with Multiple Sclerosis 7 Inflammation in Stroke Lesions 11 Microglia Activation and Macrophage Response 12 Granulocyte Infiltration 12 Conclusions 15 References 15 2 In Vivo Imaging of Glial and Immune Cell Responses in Central Nervous System Injury and Disease 21 Alexandre Paré and Steve Lacroix Introduction 21 Intravital Microscopy in the CNS and Its Challenges 22 In Vivo Imaging of the CNS Following Sterile Injury 24 In Vivo Imaging of the CNS in Disorders with an Inflammatory Component 27 Conclusion 32 Acknowledgments 33 References 33 v vi CONTENTS PART II Detrimental Aspects of Inflammation 39 3 Roles of CD4 and CD8 T Lymphocytes in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis 41 Nathalie Arbour and Alexandre Prat Introduction 41 T Lymphocytes: Central Immune Cells 42 Autoreactive T Lymphocytes 42 From Peripheral Activation to CNS Extravasation 45 Role of CD4 T Lymphocytes in MS and EAE: Th1 versus Th17 46 Role of CD8 T Lymphocytes in MS and EAE 47 Regulatory T Lymphocytes in MS and EAE 48 Conclusions 49 Acknowledgments 49 References 49 4 Microglia and Macrophage Responses and Their Role after Spinal Cord Injury 53 Antje Kroner, Andrew D. Greenhalgh, and Samuel David Introduction 53 Microglial Responses to Injury 54 Interactions between Microglia and Other Cell Types in Signaling Responses to Injury 57 Entry of Peripheral Macrophages and Differences with Microglia 59 Diverse Roles of Macrophages/Microglia in CNS Injury and Disease 60 Macrophage Polarization in SCI 61 Concluding Remarks 66 Acknowledgments 66 References 66 5 The Complexity of the Innate Immune System Activation in Stroke Pathogenesis 71 María Isabel Cuartero, Ignacio Lizasoain, María Ángeles Moro, and Ivan Ballesteros Activation of the Brain Innate Immunity After Stroke 71 Myeloid Heterogeneity in Brain Ischemia 76 Concluding Remarks 81 References 81 6 Neuroinflammation in Aging 87 Ashley M. Fenn, Diana M. Norden, and Jonathan P. Godbout Increased CNS Inflammation in Response to Immune Challenge is Adaptive and Beneficial 87 The CNS Microenvironment Shifts to a Proinflammatory State with Aging 88 Microglial Priming 88 Microglial Regulation 90 Immune Reactivity of Glia Contributes to Cognitive and Behavioral Deficits 97 Conclusions 100 References 100 CONTENTS vii 7 Peripheral and Central Immune Mechanisms in Neuropathic Pain 107 Ji Zhang Introduction 107 Inflammation in Neuropathic Pain 108 Contribution of Peripheral Immune Cells to the Pathogenesis of Neuropathic Pain 109 Critical Roles of Spinal Glial Activation in Neuropathic Pain 111 Significance of Neural Barriers in Inflammatory Response along Pain Transmission Pathway 114 Imbalance of Pro- and Anti-inflammatory Responses in Neuropathic Pain 115 Challenges in Translating Anti-inflammatory Therapeutic Strategies for the Relief of Neuropathic Pain 115 Acknowledgment 117 References 117 8 Inflammation in the Pathogenesis of Inherited Peripheral Neuropathies 123 Janos Groh, Dennis Klein, Antje Kroner, and Rudolf Martini Inherited Peripheral Neuropathies 123 Subtype-Specific Molecular Patterns of CMT1 124 Molecular Commonalities of CMT1 Subtypes–a Link to Inflammation 125 The Impact of Innate Immune Reactions in Mouse Models of CMT1 126 The Impact of Adaptive Immune Reactions in Mouse Models of CMT1 129 Implications for Putative Therapeutic Approaches 130 Synopsis 133 Acknowledgments 133 References 133 9 Obesity- and Neuroinflammation-Associated Mood and Cognitive Disorders 139 Nathalie Castanon, Giamal Luheshi, and Sophie Layé Introduction 139 Neuropsychiatric Comorbidity in Obesity 140 Animal Models of Obesity and MetS 140 Mechanisms Underlying the Association between Obesity/MetS and Neuropsychiatric Symptoms 142 Neuroinflammation, Sickness Behavior, and Neuropsychiatric Symptoms 143 Role of Neuroinflammation in Neuropsychiatric Symptoms Associated with Obesity and MetS 146 Conclusions 148 References 149 10 Viral Infections of the Central Nervous System: Pathogenic and Protective Effects of Neuroinflammation 155 John G. Walsh and Christopher Power Introduction 155 Nervous System Infection and Inflammation 157 viii CONTENTS HIV-1 Infection: Neurological and Neuropathological Features 158 WNV Infection and Neuropathology 162 Future Perspectives 166 References 167 PART III Beneficial Aspects of Inflammation 173 11 The Interplay between the Peripheral and Local Immune Response in Recovery from Acute Central Nervous System Injuries 175 Catarina Raposo and Michal Schwartz Paradigm of Protective Autoimmunity 175 Dichotomy between Microglia and Infiltrating Monocyte-Derived Macrophages 176 Infiltrating Macrophages Promote Inflammation Resolution and Axonal Regeneration 177 The Two Faces of Tregs in CNS Repair 178 Protective Autoimmunity Works at the Specialized Choroid Plexus Gate 179 Inflammation, the Old Villain in Spinal Cord Repair 181 Comprehensive View of the Protective Autoimmune Network: the Link between Autoimmune T Cells and Inflammation-Resolving Cells 181 Acknowledgments 183 References 183 12 Inflammation and Optic Nerve Regeneration 189 Lukas Andereggen, Ephraim F. Trakhtenberg, Yuqin Yin, and Larry I. Benowitz Introduction 189 Background 190 Effects of inflammation on RGC survival and Optic Nerve Regeneration 192 Oncomodulin as a Key Mediator of Inflammation-Induced Regeneration 193 Synergistic Effects of Combinatorial Treatments 198 Conclusions 200 Acknowledgments 200 References 200 13 Effects of Macrophages and Monocytes in Remyelination of the CNS 205 Muktha Natrajan, Bibiana Bielekova, and Robin J.M. Franklin Introduction 205 Myelin Debris Inhibits OPC Differentiation and Remyelination 207 Monocyte-Derived Macrophages are the Main Actors in Myelin Debris Phagocytosis 209 Switching from M1 to M2 Macrophages Promotes CNS Remyelination 211 Ageing Impairs Macrophage Function, Myelin Debris Clearance, and Remyelination 212 Macrophages Release Growth and Neurotrophic Factors that Promote Remyelination 213 Concluding Remarks 215 References 215 CONTENTS ix 14 Microglia Involvement in Rett Syndrome 221 Noël C. Derecki, James C. Cronk, and Jonathan Kipnis Introduction to Rett Syndrome and MeCP2 221 Experimental Mouse Models Used in the Study of Rett Syndrome 222 The Cellular Players in Central