Ubiquitous Over-Expression of Chromatin Remodeling Factor SRG3 Ameliorates the T Cell-Mediated Exacerbation of EAE by Modulating the Phenotypes of both Dendritic Cells and Macrophages.

Sung Won Lee,Hyun Jung Park,Sung Ho Jeon,Rho Hyun Seong,Changjin Lee,Seokmann Hong,Se-Ho Park,Hossam M Ashour

doi:10.1371/journal.pone.0132329

Abstract

Although SWI3-related gene (SRG3), a chromatin remodeling factor, is critical for various biological processes including early embryogenesis and thymocyte development, it is unclear whether SRG3 is involved in the differentiation of CD4+ T cells, the key mediator of adaptive immune responses. Because it is known that experimental autoimmune encephalomyelitis (EAE) development is determined by the activation of CD4+ T helper cells, here, we investigated the role of SRG3 in EAE development using SRG3 transgenic mouse models exhibiting two distinct SRG3 expression patterns: SRG3 expression driven by either the CD2 or β-actin promoter. We found that the outcome of EAE development was completely different depending on the expression pattern of SRG3. The specific over-expression of SRG3 using the CD2 promoter facilitated EAE via the induction of Th1 and Th17 cells, whereas the ubiquitous over-expression of SRG3 using the β-actin promoter inhibited EAE by promoting Th2 differentiation and suppressing Th1 and Th17 differentiation. In addition, the ubiquitous over-expression of SRG3 polarized CD4+ T cell differentiation towards the Th2 phenotype by converting dendritic cells (DCs) or macrophages to Th2 types. SRG3 over-expression not only reduced pro-inflammatory cytokine production by DCs but also shifted macrophages from the inducible nitric oxide synthase (iNOS)-expressing M1 phenotype to the arginase-1-expressing M2 phenotype during EAE. In addition, Th2 differentiation in β-actin-SRG3 Tg mice during EAE was associated with an increase in the basophil and mast cell populations and in IL4 production. Furthermore, the increased frequency of Treg cells in the spinal cord of β-actin-SRG3 Tg mice might induce the suppression of and accelerate the recovery from EAE symptoms. Taken together, our results provide the first evidence supporting the development of a new therapeutic strategy for EAE involving the modulation of SRG3 expression to induce M2 and Th2 polarization, thereby inhibiting inflammatory immune responses.

Highlights

The epigenetic machinery regulating the chromatin structure consists of DNA methylation, histone modification and ATP-dependent remodeling
We found that the frequency of Th1 and Th17 cells was dramatically decreased in β-actin-SRG3/MBP TCR double Tg mice compared to the control mice and that IL4-producing Th2 cells were increased in both the naive and EAE groups in these double Tg mice compared to the control mice (Fig 5A, lower panel; Fig B in S5 Fig)
We found that the infiltration of Th1 and Th17 cells into the spinal cord was significantly reduced in the β-actin-SRG3/MBP TCR double Tg mice subjected to EAE compared to the control mice (Fig 5C, lower panel)

Summary

Introduction

The epigenetic machinery regulating the chromatin structure consists of DNA methylation, histone modification and ATP-dependent remodeling. Recent findings have contributed to the identification of the influence of epigenetic modifications on the development of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE) [1]. SWI/SNF is one of the various families of ATP-dependent chromatin remodeling complexes, which regulate chromatin structure and DNA accessibility [2]. Among the diverse SWI/SNF complexes, SWI3-related gene (SRG3) is a core subunit that plays a vital role in the post-transcriptional stabilization of the major components of the SWI/SNF complex, including SNF5, BRG1, and BAF60a [3]. One previous study has shown that SWI/SNF complexes containing SRG3 and BRG1 induce the activation and proliferation of T cells via the regulation of AP-1 [7]

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