Abstract:
Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFβ, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.
摘要:
多发性硬化症(MS)是一种影响中枢神经系统(CNS)的自身免疫性脱髓鞘疾病。T辅助(Th)17细胞通过浸润CNS并产生与常驻神经胶质细胞接合的效应分子,参与MS的发病机理及其实验性自身免疫性脑脊髓炎(EAE)的动物模型。在这些神经胶质细胞中,星形胶质细胞通过响应Th17细胞释放的细胞因子和趋化因子,在协调炎症过程中发挥重要作用.在这项研究中,我们在体外和体内研究了致病性Th17细胞对星形胶质细胞的影响。我们发现Th17细胞通过部分通过Janus激酶(JAK)1依赖性机制驱动转录组变化来重新编程星形胶质细胞,其中包括增加的趋化因子,干扰素诱导基因,和细胞因子受体。在体内,我们观察到星形胶质细胞上细胞表面细胞因子受体表达的区域特异性异质性,包括IFN-γ,IL-1,TNF-α,IL-17,TGFβ,IL-10此外,这些受体在髓磷脂反应性Th17细胞过继转移诱导的EAE过程中受到动态调节。这项研究总体上提供了星形胶质细胞Th17细胞重编程的证据,这可能会导致自身免疫性神经炎症期间星形细胞对细胞因子的反应性发生变化。