Neuroinflammation

Samuel David is a Professor at the Centre for Research in Neuroscience at The Research Institute of the McGill University Health Centre in Montreal, Quebec, Canada

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 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

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
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

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 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

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 Prüss, 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