OASL 的过表达上调 TET1，通过 IRF1 信号诱导系统性硬化症中 CD4 T 细胞的异常激活。
Overexpression of OASL upregulates TET1 to induce aberrant activation of CD4 T cells in systemic sclerosis via IRF1 signaling.
机构信息
Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
出版信息
Arthritis Res Ther. 2022 Feb 19;24(1):50. doi: 10.1186/s13075-022-02741-w.
BACKGROUND
Systemic sclerosis (SSc), an autoimmune disease with unknown etiology and pathogenesis, is characterized by abnormal autoimmunity, vascular dysfunction, and progressive fibrosis of skin and organs. Studies have shown that a key factor in the pathogenesis of SSc is aberrant activation of CD4 T cells. Our previous studies have shown that a global hypomethylation state of CD4 T cells is closely related to aberrant activation. However, the exact mechanism of hypomethylation in CD4+T cells is not yet clear.
METHODS
Illumina HiSeq 2500 Platform was used to screen differentially expressed genes and explore the role of OASL, TET1, and IRF1 in the abnormal activation of CD4+T cells in SSc. Finally, double luciferase reporter gene experiments were used to analyze the interaction between IRF1 and TET1.
RESULTS
OASL overexpression could upregulate TET1 to increase the hydroxymethylation levels of CD4+ T cells and induce high expression of functional proteins (CD40L and CD70), thus promoting CD4+T cell aberrant activation. Moreover, OASL upregulated TET1 via IRF1 signaling activation, and a double luciferase reporter gene experiment revealed that IRF1 can bind to the TET1 promoter region to regulate its expression.
CONCLUSIONS
OASL participates in the regulation of abnormal hypomethylation of CD4+ T cells in SSc, which implies a pivotal role for IFN signaling in the pathogenesis of SSc. Regulating DNA methylation and IFN signaling may serve as therapeutic treatments in SSc.
背景
系统性硬化症（SSc）是一种病因和发病机制不明的自身免疫性疾病，其特征为异常自身免疫、血管功能障碍和皮肤及器官的进行性纤维化。研究表明，SSc 发病机制的一个关键因素是 CD4 T 细胞的异常激活。我们之前的研究表明，CD4 T 细胞的全基因组低甲基化状态与异常激活密切相关。然而，CD4+T 细胞低甲基化的确切机制尚不清楚。
方法
使用 Illumina HiSeq 2500 平台筛选差异表达基因，并探讨 OASL、TET1 和 IRF1 在 SSc 中 CD4+T 细胞异常激活中的作用。最后，通过双荧光素酶报告基因实验分析 IRF1 和 TET1 之间的相互作用。
结果
OASL 的过表达可上调 TET1，增加 CD4+T 细胞的羟甲基化水平，并诱导功能性蛋白（CD40L 和 CD70）的高表达，从而促进 CD4+T 细胞异常激活。此外，OASL 通过 IRF1 信号激活上调 TET1，双荧光素酶报告基因实验表明，IRF1 可以结合 TET1 启动子区域来调节其表达。
结论
OASL 参与 SSc 中 CD4+T 细胞异常低甲基化的调节，提示 IFN 信号在 SSc 发病机制中的关键作用。调节 DNA 甲基化和 IFN 信号可能成为 SSc 的治疗方法。
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