剪接因子 SRSF1 通过 RhoH 限制 IFN-γ 的产生，并改善实验性肾炎。
Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis.
机构信息
Division of Rheumatology and Clinical Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
出版信息
Rheumatology (Oxford). 2021 Jan 5;60(1):420-429. doi: 10.1093/rheumatology/keaa300.
OBJECTIVE
CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis.
METHODS
T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots.
RESULTS
Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients.
CONCLUSION
Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.
目的
产生 IFN-γ 的 CD4+辅助性 T 细胞 1（Th1）有助于系统性红斑狼疮（SLE）和狼疮性肾炎发病机制中的炎症反应。此外，在临床诊断前的数年，患者血清中 II 型 IFN 水平升高先于 I 型 IFNs 和自身抗体的出现。然而，SLE 中控制这种炎症反应的分子和机制仍不清楚。SLE 患者 T 细胞中的丝氨酸/精氨酸丰富剪接因子 1（SRSF1）减少，并抑制 T 细胞过度活跃和全身性自身免疫。我们的目的是评估 SRSF1 在 IFN-γ 产生、Th1 分化和实验性肾炎中的作用。
方法
使用 T 细胞条件性 Srsf1 敲除小鼠研究抗肾毒性血清诱导的肾炎，并通过流式细胞术评估 IFN-γ 产生和 Th1 分化。使用 RNA 测序评估转录组谱。通过电穿孔转染 siRNA 沉默人 T 细胞中的 RhoH。通过免疫印迹评估 RhoH 和 SRSF1 蛋白水平。
结果
T 细胞中 Srsf1 的缺失导致 Th1 分化增加和抗肾毒性血清肾炎加重。Srsf1 缺陷型 T 细胞中 RhoH 的表达水平降低，而在人 T 细胞中沉默 RhoH 导致 IFN-γ 产生增加。此外，SLE 患者 T 细胞中 RhoH 的表达降低且与 SRSF1 直接相关。
结论
我们的研究揭示了 SRSF1 通过控制 RhoH 在抑制 IFN-γ 产生和 Th1 分化中的先前未被认识的作用。SRSF1 的表达减少可能通过这些分子机制导致自身免疫相关肾炎的发病机制。
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