Interferon β-Mediated Protective Functions of Microglia in Central Nervous System Autoimmunity.

Stefanie Scheu,Udo Dannlowski,Shafaqat Ali,Luisa Klotz,Judith Alferink,Ritu Mann-Nüttel,Lisa Richter,Volker Arolt,Tanja Kuhlmann

doi:10.3390/ijms20010190

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and axonal damage. It often affects young adults and can lead to neurological disability. Interferon β (IFNβ) preparations represent widely used treatment regimens for patients with relapsing-remitting MS (RRMS) with therapeutic efficacy in reducing disease progression and frequency of acute exacerbations. In mice, IFNβ therapy has been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS while genetic deletion of IFNβ or its receptor augments clinical severity of disease. However, the complex mechanism of action of IFNβ in CNS autoimmunity has not been fully elucidated. Here, we review our current understanding of the origin, phenotype, and function of microglia and CNS immigrating macrophages in the pathogenesis of MS and EAE. In addition, we highlight the emerging roles of microglia as IFNβ-producing cells and vice versa the impact of IFNβ on microglia in CNS autoimmunity. We finally discuss recent progress in unraveling the underlying molecular mechanisms of IFNβ-mediated effects in EAE.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and neurodegeneration
Additional disease modifying and immunomodulatory therapies for Relapsing-remitting MS (RRMS) have been licensed. Among those glatirameracetate [34], dimethyl fumarate [35], teriflunomide [36], fingolimod (Sphingosin-1-Phosphat receptor agonist) [37], and cladribine [38], as well as the humanized monoclonal antibodies Natalizumab, that inhibits lymphocyte migration into the CNS by blocking the adhesion molecule very late antigen-4 (VLA-4) [39], Alemtuzumab, that recognizes CD52 on lymphocytes resulting in T and B cell depletion [40,41], and Ocrelizumab, an anti-CD20 antibody depleting B cells, have been approved [42]
We focus on recent advances in the identification of Interferon β (IFNβ)-producing cells and IFNβ-mediated molecular pathways in CNS autoimmunity

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and neurodegeneration. Additional disease modifying and immunomodulatory therapies for RRMS have been licensed Among those glatirameracetate [34], dimethyl fumarate [35], teriflunomide [36], fingolimod (Sphingosin-1-Phosphat receptor agonist) [37], and cladribine [38], as well as the humanized monoclonal antibodies Natalizumab, that inhibits lymphocyte migration into the CNS by blocking the adhesion molecule very late antigen-4 (VLA-4) [39], Alemtuzumab, that recognizes CD52 on lymphocytes resulting in T and B cell depletion [40,41], and Ocrelizumab, an anti-CD20 antibody depleting B cells, have been approved [42]. Induction of endogenous IFNβ production by polyinosinic:polycytidylic acid (poly(I:C)) treatment leads to reduced EAE symptoms in mice while animals deficient for IFNβ or its receptor exhibit increased clinical severity [50,51,52]. We highlight the cellular targets of this cytokine in EAE

Origin and Phenotype of Microglia and Macrophages in the CNS

Microglia Activation and Polarization in Neuroinflammation

Microglia as Producers of Endogenous IFNβ in CNS Autoimmunity

Findings

IFNβ Mediated Effects on Microglia in CNS Autoimmunity