Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
Medical Science Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Immunol. 2022 Jun 20;13:922871. doi: 10.3389/fimmu.2022.922871. eCollection 2022.
Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that plays an essential role in immune system development and autoimmune diseases. This study aimed to characterize the role of EZH2 in the pathogenesis of primary Sjögren's syndrome (pSS).
We analyzed EZH2 expression in two transcriptomic datasets of peripheral blood mononuclear cells (PBMCs) from pSS patients and healthy controls. We measured EZH2 expression in CD4 T cells, CD8 T cells, and CD19 B cells from pSS patients and healthy controls and correlated EZH2 expression with clinical parameters. We also examined the activation, proliferation, and T-cell differentiation of CD4 T cells using the EZH2 inhibitor GSK126, EZH2 siRNA, and EZH2-expressing vector. We further examined the STAT3 signaling pathway after EZH2 inhibition and detected Tfh differentiation in EZH2-overexpressed CD4 T cells with STAT3 knocked down.
EZH2 was upregulated in GSE164885 and GSE48378. EZH2 expression was higher in pSS CD4 and CD8+ T cells, and EZH2 expression in circulating pSS CD4 T cells was positively correlated with IgG, IgA, ESR, RF, and the circulating Tfh population. EZH2 inhibition and silencing EZH2 suppressed activation, proliferation, and Tfh differentiation. Furthermore, overexpressing EZH2 promoted activation, proliferation, and Tfh differentiation in CD4 T cells. EZH2 inhibition attenuated STAT3 phosphorylation in CD4 T cells. STAT3 knockdown abrogated EZH2-promoted Tfh differentiation.
EZH2 expression was abnormally elevated in pSS CD4 T cells, which facilitated Tfh differentiation of CD4 T cells by enhancing STAT3 phosphorylation. EZH2 promotes Tfh differentiation and might be implicated in pSS pathogenesis.
增强子结合锌指蛋白 2（EZH2）是一种表观遗传调节剂，在免疫系统发育和自身免疫性疾病中发挥着重要作用。本研究旨在探讨 EZH2 在原发性干燥综合征（pSS）发病机制中的作用。
我们分析了来自 pSS 患者和健康对照者的外周血单个核细胞（PBMCs）的两个转录组数据集的 EZH2 表达。我们测量了来自 pSS 患者和健康对照者的 CD4 T 细胞、CD8 T 细胞和 CD19 B 细胞中的 EZH2 表达，并将 EZH2 表达与临床参数相关联。我们还使用 EZH2 抑制剂 GSK126、EZH2 siRNA 和 EZH2 表达载体来检查 CD4 T 细胞的激活、增殖和 T 细胞分化。我们进一步在 EZH2 抑制后检测 STAT3 信号通路，并在 EZH2 过表达的 CD4 T 细胞中敲低 STAT3 检测 Tfh 分化。
EZH2 在 GSE164885 和 GSE48378 中上调。pSS CD4 和 CD8+T 细胞中 EZH2 表达较高，pSS 循环 CD4 T 细胞中的 EZH2 表达与 IgG、IgA、ESR、RF 和循环 Tfh 群体呈正相关。EZH2 抑制和沉默 EZH2 抑制了激活、增殖和 Tfh 分化。此外，EZH2 过表达促进了 CD4 T 细胞的激活、增殖和 Tfh 分化。EZH2 抑制减弱了 CD4 T 细胞中 STAT3 的磷酸化。STAT3 敲低消除了 EZH2 促进的 Tfh 分化。
pSS CD4 T 细胞中 EZH2 表达异常升高，通过增强 STAT3 磷酸化促进 CD4 T 细胞的 Tfh 分化。EZH2 促进 Tfh 分化，可能与 pSS 发病机制有关。
