Neuroinflammation E-Book

Samuel David

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 728

Veröffentlichungsjahr: 2015

Beschreibung

Neuroinflammation has long been studied for its connection to the development and progression of Multiple Sclerosis. In recent years, the field has expanded to look at the role of inflammatory processes in a wide range of neurological conditions and cognitive disorders including stroke, amyotrophic lateral sclerosis, and autism. Researchers have also started to note the beneficial impacts of neuroinflammation in certain diseases.

Neuroinflammation: New Insights into Beneficial and Detrimental Functions provides a comprehensive view of both the detriments and benefits of neuroinflammation in human health.

Neuroinflammation: New Insights into Beneficial and Detrimental Functions opens with two chapters that look at some fundamental aspects of neuroinflammation in humans and rodents. The remainder of the book is divided into two sections which examine both the detrimental and beneficial aspects of inflammation on the brain, spinal cord and peripheral nerves, on various disease states, and in normal aging. These sections provide a broad picture of the role neuroinflammation plays in the physiology and pathology of various neurological disorders.

Providing cross-disciplinary coverage, Neuroinflammation: New Insights into Beneficial and Detrimental Functions will be an essential volume for neuroimmunologists, neurobiologists, neurologists, and others interested in the field.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Contributors

Preface

Part I: Introduction

Chapter 1: Immune Response in the Human Central Nervous System in Multiple Sclerosis and Stroke

Introduction

The Concept of Neuroinflammation

Basic Principles of Immune Surveillance and Inflammation by Adaptive Immune Responses

Inflammation in the Central Nervous System of Patients with Multiple Sclerosis

Inflammation in Stroke Lesions

Microglia Activation and Macrophage Response

Granulocyte Infiltration

Conclusions

References

Chapter 2: In Vivo Imaging of Glial and Immune Cell Responses in Central Nervous System Injury and Disease

Introduction

Intravital Microscopy in the CNS and Its Challenges

In Vivo

Imaging of the CNS Following Sterile Injury

In Vivo

Imaging of the CNS in Disorders with an Inflammatory Component

Conclusion

Acknowledgments

References

Part II: Detrimental Aspects of Inflammation

Chapter 3: Roles of CD4 and CD8 T Lymphocytes in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Introduction

T Lymphocytes: Central Immune Cells

Autoreactive T Lymphocytes

From Peripheral Activation to CNS Extravasation

Role of CD4 T Lymphocytes in MS and EAE: Th1 versus Th17

Role of CD8 T Lymphocytes in MS and EAE

Regulatory T Lymphocytes in MS and EAE

Conclusions

Acknowledgments

References

Chapter 4: Microglia and Macrophage Responses and Their Role after Spinal Cord Injury

Introduction

Microglial Responses to Injury

Interactions between Microglia and Other Cell Types in Signaling Responses to Injury

Entry of Peripheral Macrophages and Differences with Microglia

Diverse Roles of Macrophages/Microglia in CNS Injury and Disease

Macrophage Polarization in SCI

Concluding Remarks

Acknowledgments

References

Chapter 5: The Complexity of the Innate Immune System Activation in Stroke Pathogenesis

Activation of the Brain Innate Immunity After Stroke

Myeloid Heterogeneity in Brain Ischemia

Concluding Remarks

References

Chapter 6: Neuroinflammation in Aging

Increased CNS Inflammation in Response to Immune Challenge is Adaptive and Beneficial

The CNS Microenvironment Shifts to a Proinflammatory State with Aging

Microglial Priming

Microglial Regulation

Immune Reactivity of Glia Contributes to Cognitive and Behavioral Deficits

Conclusions

References

Chapter 7: Peripheral and Central Immune Mechanisms in Neuropathic Pain

Introduction

Inflammation in Neuropathic Pain

Contribution of Peripheral Immune Cells to the Pathogenesis of Neuropathic Pain

Critical Roles of Spinal Glial Activation in Neuropathic Pain

Significance of Neural Barriers in Inflammatory Response along Pain Transmission Pathway

Imbalance of Pro- and Anti-inflammatory Responses in Neuropathic Pain

Challenges in Translating Anti-inflammatory Therapeutic Strategies for the Relief of Neuropathic Pain

Acknowledgment

References

Chapter 8: Inflammation in the Pathogenesis of Inherited Peripheral Neuropathies

Inherited Peripheral Neuropathies

Subtype-Specific Molecular Patterns of CMT1

Molecular Commonalities of CMT1 Subtypes – a Link to Inflammation

The Impact of Innate Immune Reactions in Mouse Models of CMT1

The Impact of Adaptive Immune Reactions in Mouse Models of CMT1

Implications for Putative Therapeutic Approaches

Synopsis

Acknowledgments

References

Chapter 9: Obesity- and Neuroinflammation-Associated Mood and Cognitive Disorders

Introduction

Neuropsychiatric Comorbidity in Obesity

Animal Models of Obesity and MetS

Mechanisms Underlying the Association between Obesity/MetS and Neuropsychiatric Symptoms

Neuroinflammation, Sickness Behavior, and Neuropsychiatric Symptoms

Role of Neuroinflammation in Neuropsychiatric Symptoms Associated with Obesity and MetS

Conclusions

References

Chapter 10: Viral Infections of the Central Nervous System: Pathogenic and Protective Effects of Neuroinflammation

Introduction

Nervous System Infection and Inflammation

HIV-1 Infection: Neurological and Neuropathological Features

WNV Infection and Neuropathology

Future Perspectives

References

Part III: Beneficial Aspects of Inflammation

Chapter 11: The Interplay between the Peripheral and Local Immune Response in Recovery from Acute Central Nervous System Injuries

Paradigm of Protective Autoimmunity

Dichotomy between Microglia and Infiltrating Monocyte-Derived Macrophages

Infiltrating Macrophages Promote Inflammation Resolution and Axonal Regeneration

The Two Faces of Tregs in CNS Repair

Protective Autoimmunity Works at the Specialized Choroid Plexus Gate

Inflammation, the Old Villain in Spinal Cord Repair

Comprehensive View of the Protective Autoimmune Network: the Link between Autoimmune T Cells and Inflammation-Resolving Cells

Acknowledgments

References

Chapter 12: Inflammation and Optic Nerve Regeneration

Introduction

Background

Effects of Inflammation on RGC Survival and Optic Nerve Regeneration

Oncomodulin as a Key Mediator of Inflammation-Induced Regeneration

Synergistic Effects of Combinatorial Treatments

Conclusions

Acknowledgments

References

Chapter 13: Effects of Macrophages and Monocytes in Remyelination of the CNS

Introduction

Myelin Debris Inhibits OPC Differentiation and Remyelination

Monocyte-Derived Macrophages are the Main Actors in Myelin Debris Phagocytosis

Switching from M1 to M2 Macrophages Promotes CNS Remyelination

Ageing Impairs Macrophage Function, Myelin Debris Clearance, and Remyelination

Macrophages Release Growth and Neurotrophic Factors that Promote Remyelination

Concluding Remarks

References

Chapter 14: Microglia Involvement in Rett Syndrome

Introduction to Rett Syndrome and MeCP2

Experimental Mouse Models Used in the Study of Rett Syndrome

The Cellular Players in Central Nervous System Pathology of Rett Syndrome

Microglia: From Footnote to First-Line

Microglia: the Tissue-Resident Macrophages of the Brain

Replacement/Augmentation of MICROGLIA as A Potential Therapy in Rett Syndrome

Gene Therapy

Conclusions

References

Chapter 15: The Role of Regulatory T Cells and Microglia in Amyotrophic Lateral Sclerosis

Overview of Amyotrophic Lateral Sclerosis

Overview of ALS Animal Models

Overview of Regulatory T Cells

Immunologic Aspects of Microglia and Tregs in ALS

T Cells and ALS

Tregs and ALS

Cytokines and ALS

Conclusions

References

Chapter 16: An Adaptive Role for TNFα in Synaptic Plasticity and Neuronal Function

Introduction

Developmental Roles of TNFα

TNFα in Presynaptic Function

TNFα Effects on Postsynaptic Receptor Trafficking

TNFα and Synaptic Plasticity

Glial Release of TNFα During Plasticity

TNFα-Mediated Homeostatic Plasticity

in Vivo

TNFα-Mediated Plasticity in the Striatum

Implications of TNFα-Mediated Synaptic Regulation

References

Chapter 17: Resolution of Inflammation in the Lesioned Central Nervous System

Introduction

Mechanisms of Resolution

Resolution Deficit Following CNS Lesions

Immunobiology of Resolution in CNS Lesions – Impaired Resolution Contributes to Neuropathology

Late Degeneration/“Tertiary” Injury and Autoimmunity as a Consequence of Failed Resolution of Inflammation in CNS Lesions?

Evidence for the Effectiveness of Pro-resolution Mediators in CNS Lesions

Conclusion

Acknowledgment

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Part I: Introduction

Begin Reading

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 2.1

Figure 2.2

Figure 3.1

Figure 4.1

Figure 4.2

Figure 5.1

Figure 5.2

Figure 6.1

Figure 6.2

Figure 6.3

Figure 7.1

Figure 8.1

Figure 8.2

Figure 8.3

Figure 9.1

Figure 9.2

Figure 9.3

Figure 10.1

Figure 10.2

Figure 11.1

Figure 12.1

Figure 12.2

Figure 12.3

Figure 13.1

Figure 13.2

Figure 13.3

Figure 14.1

Figure 15.1

Figure 15.2

Figure 16.1

Figure 17.1

Figure 17.2

Figure 17.3

List of Tables

Table 2.1

Table 5.1

Table 13.1

Table 14.1

Table 16.1

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, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

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Library of Congress Cataloging-in-Publication Data:

Neuroinflammation (David)

Neuroinflammation : new insights into beneficial and detrimental functions / edited by Samuel David.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-73282-3 (cloth)

I. David, Samuel, editor. II. Title.

[DNLM: 1. 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

Contributors

Stanley H. Appel

Department of Neurology

Methodist Neurological Institute

The Methodist Hospital

Weill Cornell Medical College

Houston, TX, USA

Nathalie Arbour

Department of Neurosciences

Université de Montréal

Centre de Recherche du Centre Hospitalier de l'Université de Montréal

Montreal, QC, Canada

Lukas Andereggen

Laboratories for Neuroscience Research in Neurosurgery and F.M. Kirby Neurobiology Center

Boston Children's Hospital

Boston, MA, USA

Department of Neurosurgery

Harvard Medical School

Boston, MA, USA

Ivan Ballesteros

Department of Pharmacology (Medical School)

Universidad Complutense de Madrid

Instituto de Investigación Hospital 12 de Octubre (i+12)

Madrid, Spain

David R. Beers

Department of Neurology

Methodist Neurological Institute

The Methodist Hospital

Weill Cornell Medical College

Houston, TX, USA

Larry I. Benowitz

Laboratories for Neuroscience Research in Neurosurgery and F.M. Kirby Neurobiology Center

Boston Children's Hospital

Boston, MA, USA

Departments of Neurosurgery and Ophthalmology

Program in Neuroscience

Harvard Medical School

Boston, MA, USA

Bibiana Bielekova

Neuroimmunology Branch

National Institute of Neurological Disorders and Stroke

National Institutes of Health

Bethesda, MD, USA

Nathalie Castanon

Laboratory of Nutrition and Integrative Neurobiology

INRA UMR 1286

Bordeaux, France

University of Bordeaux

Bordeaux, France

María Isabel Cuartero

Department of Pharmacology (Medical School)

Universidad Complutense de Madrid

Instituto de Investigación Hospital 12 de Octubre (i+12)

Madrid, Spain

James C. Cronk

Center for Brain Immunology and Glia and Department of Neuroscience

University of Virginia School of Medicine

Charlottesville, VA, USA

Samuel David

Department of Neurology and Neurosurgery

Faculty of Medicine

Centre for Research in Neuroscience

The Research Institute of the McGill University Health Centre

Montreal, QC, Canada

Noël C. Derecki

Center for Brain Immunology and Glia and Department of Neuroscience

University of Virginia School of Medicine

Charlottesville, VA, USA

Ashley M. Fenn

Department of Neuroscience

The Ohio State University

Columbus, OH, USA

Robin J.M. Franklin

Department of Clinical Neurosciences

Wellcome Trust-MRC Cambridge Stem Cell Institute

University of Cambridge

Cambridge, UK

Andrew D. Greenhalgh

Department of Neurology and Neurosurgery

Faculty of Medicine

Centre for Research in Neuroscience

The Research Institute of the McGill University Health Centre

Montreal, QC, Canada

Jonathan P. Godbout

Department of Neuroscience and Institute for Behavioral Medicine Research

The Ohio State University

Columbus, OH, USA

Janos Groh

Department of Neurology and Developmental Neurobiology

University of Wuerzburg

Wuerzburg, Germany

Renu Heir

Department of Neurology and Neurosurgery

Centre for Research in Neuroscience

The Research Institute of the McGill University Health Center

Montreal, QC, Canada

Kristopher G. Hooten

Department of Neurological Surgery

University of Florida

Gainesville, FL, USA

Dennis Klein

Department of Neurology and Developmental Neurobiology

University of Wuerzburg

Wuerzburg, Germany

Jonathan Kipnis

Center for Brain Immunology and Glia and Department of Neuroscience

University of Virginia School of Medicine

Charlottesville, VA, USA

Graduate Program in Neuroscience and Medical Scientist Training Program

University of Virginia School of Medicine

Charlottesville, VA, USA

Antje Kroner

Department of Neurology and Developmental Neurobiology

University of Wuerzburg

Wuerzburg, Germany

Department of Neurology and Neurosurgery

Faculty of Medicine

Centre for Research in Neuroscience

The Research Institute of the McGill University Health Centre

Montreal, QC, Canada

Steve Lacroix

Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec –CHUL

Québec, QC, Canada

Département de Médecine Moléculaire

Faculté de médecine

Université Laval

Québec, QC, Canada

Hans Lassman

Division of Neuroimmunology

Center for Brain Research

Medical University of Vienna

Vienna, Austria

Sophie Layé

Laboratory of Nutrition and Integrative Neurobiology

INRA UMR 1286

Bordeaux, France

University of Bordeaux

Bordeaux, France

Ignacio Lizasoain

Department of Pharmacology (Medical School)

Universidad Complutense de Madrid

Instituto de Investigación Hospital 12 de Octubre (i+12)

Madrid, Spain

Giamal Luheshi

Department of Psychiatry

Douglas Mental Health University Institute

McGill University

Montreal, QC, Canada

Rudolf Martini

Department of Neurology and Developmental Neurobiology

University of Wuerzburg

Wuerzburg, Germany

María Ángeles Moro

Department of Pharmacology (Medical School)

Universidad Complutense de Madrid

Instituto de Investigación Hospital 12 de Octubre (i+12)

Madrid, Spain

Muktha Natrajan

Department of Clinical Neurosciences

Wellcome Trust-MRC Cambridge Stem Cell Institute

University of Cambridge

Cambridge, UK

Diana M. Norden

Department of Neuroscience

The Ohio State University

Columbus, OH, USA

Alexandre Paré

Centre de Recherche du Centre Hospitalier Universitaire (CHU) de Québec - CHUL

Québec, QC, Canada

Alexandre Prat

Department of Neurosciences

Université de Montréal

Centre de Recherche du Centre Hospitalier de l'Université de Montréal

Montreal, QC, Canada

Christopher Power

Department of Medicine (Neurology)

University of Alberta

Edmonton, AB, Canada

Harald Prüss

Department of Neurology and Experimental Neurology

Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology)

Charite

Universitatsmedizin Berlin

Berlin, Germany

German Center for Neurodegenerative Diseases (DZNE)

Berlin, Germany

Catarina Raposo

Department of Neurobiology

Weizmann Institute of Science

Rehovot, Israel

Jan M. Schwab

Department of Neurology and Experimental Neurology

Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology)

Charite - Universitatsmedizin Berlin

Berlin, Germany

Spinal Cord Injury Center

Trauma Hospital Berlin

Berlin, Germany

Department of Neurology and Neuroscience

Center for Brain and Spinal Cord Repair

The Ohio State University Medical Center

Columbus, OH, USA

Michal Schwartz

Department of Neurobiology

Weizmann Institute of Science

Rehovot, Israel

Charles N. Serhan

Department of Anesthesiology

Perioperative and Pain Medicine

Center for Experimental Therapeutics and Reperfusion Injury

Harvard Institutes of Medicine

Brigham and Women's Hospital and Harvard Medical School

Boston, MA, USA

David Stellwagen

Department of Neurology and Neurosurgery

Centre for Research in Neuroscience

The Research Institute of the McGill University Health Center

Montreal, QC, Canada

Ephraim F. Trakhtenberg

Laboratories for Neuroscience Research in Neurosurgery and F.M. Kirby Neurobiology Center

Boston Children's Hospital

Boston, MA, USA

Department of Neurosurgery

Harvard Medical School

Boston, MA, USA

John G. Walsh

Department of Medicine (Neurology)

University of Alberta

Edmonton, AL, Canada

Yuqin Yin

Laboratories for Neuroscience Research in Neurosurgery and F.M. Kirby Neurobiology Center

Boston Children's Hospital

Boston, MA, USA

Department of Neurosurgery

Harvard Medical School

Boston, MA, USA

Ji Zhang

The Alan Edwards Centre for Research on Pain and Department of Neurology and Neurosurgery

Faculty of Dentistry and Medicine

McGill University

Montreal, QC, Canada

Weihua Zhao

Department of Neurology

Houston Methodist Neurological Institute

Houston Methodist Hospital Research Institute

Houston Methodist Hospital

Houston, TX, USA

Preface

When I was approached by the publisher, Wiley, to edit a book on neuroinflammation I felt it was a timely project and one that would have a wide appeal. As a researcher whose work focuses on inflammation in spinal cord injury (SCI), central nervous system (CNS) autoimmune disease, peripheral nerve injury, and stroke, I have a broad perspective on the role of neuroinflammation. Moreover, as someone who has run a graduate level course on neuroinflammation for the past 10 years at McGill University, I have had a close-up view of the wide ranging impact of inflammation in neurology.

This book is divided into three sections. The first part begins with two general chapters, the first chapter provides a broad overview of neuroinflammation and immune pathology in patients with multiple sclerosis (MS) and stroke. It discusses the concept of neuroinflammation and the basic principles of immune surveillance and inflammation by adaptive immune responses. The second chapter provides an overview of in vivo imaging of immune and glial cell responses in animal models of CNS injury and disease. The use of intravital microscopy to study CNS inflammation is providing new insights into cell-to-cell interactions and behavior of immune and CNS cells in situ. The second part of the book focuses mainly on the detrimental aspects of inflammation, although discussions in many chapters also note some of the beneficial aspects of inflammation that one could modulate to improve outcomes. This section consists of eight chapters ranging from MS and experimental autoimmune encephalomyelitis, SCI, stroke, aging, obesity, neuropathic pain subsequent to peripheral nerve injury, inherited peripheral neuropathies, and CNS viral infections such as human immunodeficiency virus (HIV) and West Nile virus. The third part of the book focuses on areas in which the beneficial aspects of neuroinflammation are seen more prominently. This section consists of seven chapters ranging from CNS injury, remyelination in the CNS, Rett syndrome, amyotrophic lateral sclerosis (ALS), and the role of tumor necrosis factor (TNF) in synaptic plasticity and neuronal function. The book ends with a chapter on the mechanisms underlying resolution of inflammation in CNS. The key reasons for choosing these topics are summarized in the subsequent text and will give the reader an idea of the main objectives of this book.

It is becoming increasingly evident that inflammation plays a role in many if not most neurological disorders. Certain conditions such as MS have long been recognized as a neuroinflammatory condition involving a prominent autoimmune response to CNS myelin antigens. In the case of traumatic SCI and stroke, inflammation triggered locally at the site of injury or stroke has also been recognized as contributing to secondary tissue damage and evolving pathology. Studies on neuroinflammation in MS, SCI, and stroke have a long history, but several recent advances have begun to shed new light that is worth taking note of. In contrast, the involvement of neuroinflammation has not been widely appreciated in aging and obesity. In these areas, neuroinflammation can impact on learning and memory, as well as on mood and cognitive function. With the increase in wealth in formerly developing countries, obesity is increasing worldwide at a shocking rate in children and adults and has an impact not only on cardiovascular health and the development of type 2 diabetes but also on the brain. In HIV/acquired immunodeficiency syndrome (AIDS), despite the effectiveness of combined antiretroviral therapy to markedly improve survival of people with HIV/AIDS, the CNS remains a major reservoir of the virus. About a third of patients on antiretroviral therapy have a spectrum of neurocognitive disorders that contributes significantly to morbidity and mortality and remains an important therapeutic target. Inflammation in peripheral nerves also contributes to pathology as seen in its involvement in neuropathic pain. Interestingly, this involves not only macrophage and cytokine responses locally in the injured nerve but also injury-induced microglia/macrophage and cytokine responses in the spinal cord, which provides multiple novel therapeutic targets for the management of pain. Recent work on inherited peripheral neuropathies, such as Charcot-Marie-Tooth disease, has also shown the involvement of the innate and adaptive immune response in the pathogenesis. Such work has led to the identification of immune cells as mediators and amplifiers of the demyelinating and axonal pathology.

Not too long ago there were long and heated debates on whether inflammation in conditions such as CNS injury is good or bad. One exciting development in other fields of immunology in the past decade that has now trickled into neuroscience, shows that the immune response can be good or bad depending on the state of activation of macrophages and microglia, which is influenced by the tissue environment. The idea that macrophages and microglia are very plastic cells that change their phenotype or polarization state along a continuum from proinflammatory, cytotoxic M1 phenotype at one extreme to an anti-inflammatory, pro-repair M2 phenotype at the other extreme with stages in-between is an important conceptual model with increasing supportive evidence. These cells can be polarized differently in different conditions and can also change their polarization state at different times during the evolving pathology. Macrophage and microglial polarization therefore has wide-ranging implications for neurological conditions. This includes neuroinflammation in SCI and stroke, as well as diverse phenomenon such as remyelination in the CNS, and neuronal survival in neurodegenerative diseases such as ALS. A characteristic feature of the adult mammalian CNS is that axons damaged by injury or disease fail to regenerate in situ. Work done on the optic nerve show that induction of an inflammatory response in the eye triggers long-distance axon regeneration of retinal ganglion cells through the optic nerve, showing how some aspects of neuroinflammation can indeed be beneficial to recovery. In another striking discovery, the transplantation of wild type microglia-like cells into the brains of Mecp2-null mice (a model of Rett syndrome) improved survival and motor function. Genetic targeting of microglia to express wild type Mecp2 in Mecp2-null mice also improved outcome, showing that CNS resident immune cells can be selectively targeted to improve neuronal survival in certain conditions. Another surprising recent discovery is the finding that the proinflammatory cytokine TNF can have profound effects on synaptic plasticity and neuronal function, in particular, the compensatory synaptic adaption in response to prolonged changes in neuronal activity. This has implications for neuronal function in CNS injury and disease in which increases in TNF occur. Finally, no discussion on inflammation would be complete without a section on the active resolution of inflammation and the pro-resolution bioactive lipid mediators such as resolvins and protectins that attenuate inflammation and improve outcome. There is excitement and hope that these pro-resolution mediators will become important therapeutics to treat a variety of neuroinflammatory conditions.

The reader will find differences but also many commonalities in the inflammatory responses in the various neurological conditions covered in this book. This implies that development of treatments against particular neuroinflammation targets for one neurological condition is likely to also be useful for other conditions. Many of us focus our work in our own particular areas of interest and tend to keep to our own silos. My aim is to bring such diverse areas together in one book and to break down these barriers and foster cross-talk and understanding of neuroinflammation in various fields. There is much we can learn from each other.

I want to thank all the authors for taking the time to contribute to this book. I know how much demand there is on their time and am truly appreciative of their efforts. I am indebted to Dr. Antje Kroner, a senior postdoctoral fellow in my laboratory for so generously helping me in editing the chapters and for her keen attention to detail. I could not have done it as easily without her help. I also want to thank Justin Jeffryes, Editorial Director at Wiley for seeking me out for this project. I thank him for his help, advice, and encouragement in taking this project through to completion. I am also grateful to Stephanie Dollan, Senior Editorial Assistant, for making sure I kept on track, for corresponding with the authors, and for making it all so easy.

Samuel David, PhDMontreal, Canada

Part I

Introduction

Chapter 1Immune Response in the Human Central Nervous System in Multiple Sclerosis and Stroke

Hans Lassmann

Division of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Wien, Austria

Introduction

Traditional pathology provides a clear distinction between inflammatory and neurodegenerative disorders. Inflammatory diseases comprise a large spectrum of infectious and autoimmune diseases. In these conditions, a specific immune response against autoantigens or infectious agents is present, which induces inflammation and specific destruction of cells, which contain the inciting agent or autoantigen. In addition, cells and tissue components, which are present in the vicinity of the specific targets of the immune response, also get injured or destroyed by toxic products or mediators of the immune response, a process termed “bystander damage” (Wisniewski and Bloom, 1975). In contrast, in conditions of neurodegeneration or brain ischemia, the primary cause of cell and tissue injury is due to primary metabolic changes. Also, in these conditions, immune mediators, such as cytokines or activated cells of the immune system, as for instance granulocytes or activated macrophages and microglia, are involved in cell and tissue degeneration. This lead to the broad concept of “neuroinflammation” playing a major role in the pathogenesis of a wide spectrum of brain diseases and being a potential target for neuroprotective treatments (Craft ., 2005, Ransohoff and Liu, 2007).