The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS. VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling.

中文翻译：

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VGLL3通过靶向Hippo通路调节类风湿关节炎患者成纤维样滑膜细胞中的I型干扰素特征

在类风湿性关节炎 (RA) 患者中，由 I 型 IFN（即 I 型 IFN 特征）诱导的干扰素 (IFN) 刺激基因的上调对早期诊断和治疗反应的预测具有重要意义。然而，在 RA 中调节 I 型 IFN 特征的因素在很大程度上是未知的。在这项研究中，我们旨在探索 VGLL3（果蝇中退化样基因的同源物和 Hippo 途径的推定调节剂）在调节成纤维细胞样滑膜细胞（FLS）中 I 型 IFN 特征的作用。类风湿关节炎患者。FLS 分离自 RA 和骨关节炎 (OA) 患者。通过免疫组织化学和PCR分析滑膜组织和FLS中VGLL3的表达。在 VGLL3 过表达后，在 RA-FLS 中进行 RNA 测序。通过PCR和Western印迹检查IFN刺激基因的表达。与 OA 相比，VGLL3 在 RA 滑膜和 RA-FLS 中上调。VGLL3 的过表达促进了 RA-FLS 中 IFN 刺激基因的表达。与 OA 相比，RA 滑膜中 STAT1 和 MX1 的表达也上调，并且与 RA 和 OA 患者中 VGLL3 的表达有关。VGLL3 促进了 RA-FLS 中 IRF3 的激活和 IFN-β1 的表达。增加的 IFN-β1 以自分泌方式诱导 RA-FLS 中 IFN 刺激基因的表达。VGLL3 还调节 Hippo 通路分子 WWTR1 和 AMOTL2 的表达，这介导了 VGLL3 在 RA-FLS 中对 IRF3 活化和 IFN-β1 产生的调节。