α-Synuclein deficiency promotes neuroinflammation by increasing Th1 cell-mediated immune responses

Benjamin Ettle,Alana Hoffmann,Stefanie Jörg,Ralf A Linker,Jürgen Winkler,Kristina Kuhbandner

doi:10.1186/s12974-016-0694-4

Abstract

BackgroundIncreased α-synuclein immunoreactivity has been associated with inflammatory activity in multiple sclerosis (MS) lesions, but the function of α-synuclein in neuroinflammation remains unknown. The aim of this study was to examine the role of α-synuclein in immunological processes in murine experimental autoimmune encephalomyelitis (EAE) as a model of MS.FindingsWe studied EAE in wildtype (aSyn+/+) and α-synuclein knockout (aSyn−/−) mice on a C57BL/6N background. In the spleen and spinal cord of aSyn+/+ mice, we observed a gradual reduction of α-synuclein expression during EAE, starting already in the pre-symptomatic disease phase. Compared to aSyn+/+ mice, aSyn−/− mice showed an earlier onset of symptoms but no differences in symptom severity at the peak of disease. Earlier symptom onset was accompanied by increased spinal cord infiltration of CD4+ T cells, predominantly of interferon-γ-producing T helper 1 (Th1) cells, and reduced infiltration of regulatory T cells, whereas antigen-presenting cells were unaltered. Pre-symptomatically, aSyn−/− mice exhibited hyperproliferative CD4+ splenocytes consistent with increased splenic interleukin-2 mRNA expression, resulting in increased numbers of Th1 cells in the spleen at the onset of symptoms.ConclusionsOur findings indicate a functional role of α-synuclein in early EAE by increasing Th1 cell-mediated immune response.

Highlights

Multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE) are characterized by a primarily T cell-mediated autoimmune attack against oligodendrocytes and myelin of the central nervous system (CNS), subsequently leading to axonal degeneration and neuronal loss
Α-synuclein is predominantly expressed in neurons [1], but expression has been observed in glia [1, 2] and hematopoietic cells such as T cells and monocytes [3, 4]
We initially examined α-synuclein messenger RNA expression in the spinal cord and spleen in the pre-symptomatic and acute phase of EAE in aSyn+/+ mice (Fig. 1a)

Summary

Introduction

Multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE) are characterized by a primarily T cell-mediated autoimmune attack against oligodendrocytes and myelin of the central nervous system (CNS), subsequently leading to axonal degeneration and neuronal loss. The aim of this study was to examine the role of α-synuclein in immunological processes in murine experimental autoimmune encephalomyelitis (EAE) as a model of MS. Findings: We studied EAE in wildtype (aSyn+/+) and α-synuclein knockout (aSyn−/−) mice on a C57BL/6N background. In the spleen and spinal cord of aSyn+/+ mice, we observed a gradual reduction of α-synuclein expression during EAE, starting already in the pre-symptomatic disease phase. Pre-symptomatically, aSyn−/− mice exhibited hyperproliferative CD4+ splenocytes consistent with increased splenic interleukin-2 mRNA expression, resulting in increased numbers of Th1 cells in the spleen at the onset of symptoms

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