List of 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 Pare 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
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
Acknowledgements 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
Acknowledgements 66
References 66
5 The Complexity of the Innate Immune System Activation in Stroke Pathogenesis 71
Maria Isabel Cuartero, Ignacio Lizasoain, Maria Angeles 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
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
Acknowledgement 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 132
Acknowledgements 132
References 133
9 Obesity- and Neuroinflammation-Associated Mood and Cognitive Disorders 139
Nathalie Castanon, Giamal Luheshi, and Sophie Laye
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
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, Yin Yuqin, 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
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 Nervous System Pathology of Rett Syndrome 223
Microglia: From Footnote to First-Line 224
Microglia: the Tissue-Resident Macrophages of the Brain 225
Replacement/Augmentation of MICROGLIA as A potential therapy in Rett Syndrome 228
Gene Therapy 229
Conclusions 230
References 230
15 The Role of Regulatory T Cells and Microglia in Amyotrophic Lateral Sclerosis 235
David R. Beers, Weihua Zhao, Kristopher G. Hooten, and Stanley H. Appel
Overview of Amyotrophic Lateral Sclerosis 235
Overview of ALS Animal Models 237
Overview of Regulatory T Cells 238
Immunologic Aspects of Microglia and Tregs in ALS 240
T Cells and ALS 242
Tregs and ALS 243
Cytokines and ALS 244
Conclusions 245
References 247
16 An Adaptive Role for TNFin Synaptic Plasticity and Neuronal Function 251
Renu Heir and David Stellwagen
Introduction 251
Developmental Roles of TNF? 252
TNF? in Presynaptic Function 252
TNF? effects on postsynaptic receptor trafficking 252
TNF? and Synaptic Plasticity 255
Glial Release of TNF? During Plasticity 256
TNF?-mediated homeostatic plasticity in vivo 258
TNF?-Mediated Plasticity in the Striatum 258
Implications of TNF?-Mediated Synaptic Regulation 259
References 260
17 Resolution of Inflammation in the Lesioned Central Nervous System 265
Jan M. Schwab, Harald Pruss, and Charles N Serhan
Introduction 265
Mechanisms of Resolution 267
Resolution Deficit Following CNS Lesions 268
Immunobiology of Resolution in CNS Lesions-Impaired Resolution Contributes to Neuropathology 269
Late Degeneration/"Tertiary" Injury and Autoimmunity as a Consequence of Failed Resolution of Inflammation in CNS Lesions? 271
Evidence for the Effectiveness of Pro-resolution Mediators in CNS Lesions 273
Conclusion 274
Acknowledgement 275
References 275
Index 281
