Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria; Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria.
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria.
J Autoimmun. 2018 Jan;86:51-61. doi: 10.1016/j.jaut.2017.09.008. Epub 2017 Sep 28.
Multiple sclerosis (MS) is a human neurodegenerative disease characterized by the invasion of autoreactive T cells from the periphery into the CNS. Application of pan-histone deacetylase inhibitors (HDACi) ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model for MS, suggesting that HDACi might be a potential therapeutic strategy for MS. However, the function of individual HDAC members in the pathogenesis of EAE is not known. In this study we report that mice with a T cell-specific deletion of HDAC1 (using the Cd4-Cre deleter strain; HDAC1-cKO) were completely resistant to EAE despite the ability of HDAC1cKO CD4 T cells to differentiate into Th17 cells. RNA sequencing revealed STAT1 as a prominent upstream regulator of differentially expressed genes in activated HDAC1-cKO CD4 T cells and this was accompanied by a strong increase in phosphorylated STAT1 (pSTAT1). This suggests that HDAC1 controls STAT1 activity in activated CD4 T cells. Increased pSTAT1 levels correlated with a reduced expression of the chemokine receptors Ccr4 and Ccr6, which are important for the migration of T cells into the CNS. Finally, EAE susceptibility was restored in WT:HDAC1-cKO mixed BM chimeric mice, indicating a cell-autonomous defect. Our data demonstrate a novel pathophysiological role for HDAC1 in EAE and provide evidence that selective inhibition of HDAC1 might be a promising strategy for the treatment of MS.
多发性硬化症（MS）是一种人类神经退行性疾病，其特征是自身反应性 T 细胞从外周侵入中枢神经系统。泛组蛋白去乙酰化酶抑制剂（HDACi）的应用改善了实验性自身免疫性脑脊髓炎（EAE），即 MS 的动物模型，这表明 HDACi 可能是 MS 的一种潜在治疗策略。然而，个别 HDAC 成员在 EAE 发病机制中的功能尚不清楚。在这项研究中，我们报告称，尽管 HDAC1-cKO CD4 T 细胞能够分化为 Th17 细胞，但 T 细胞特异性缺失 HDAC1 的小鼠（使用 Cd4-Cre 缺失株；HDAC1-cKO）对 EAE 完全具有抗性。RNA 测序显示 STAT1 是激活的 HDAC1-cKO CD4 T 细胞中差异表达基因的显著上游调节剂，这伴随着磷酸化 STAT1（pSTAT1）的强烈增加。这表明 HDAC1 控制激活的 CD4 T 细胞中的 STAT1 活性。增加的 pSTAT1 水平与趋化因子受体 Ccr4 和 Ccr6 的表达减少相关，这对于 T 细胞向中枢神经系统的迁移很重要。最后，在 WT：HDAC1-cKO 混合 BM 嵌合小鼠中恢复了 EAE 的易感性，表明存在细胞自主缺陷。我们的数据表明 HDAC1 在 EAE 中的新病理生理作用，并提供了选择性抑制 HDAC1 可能是治疗 MS 的有前途策略的证据。
