Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 1090, Vienna, Austria.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
Lab Invest. 2019 May;99(5):648-658. doi: 10.1038/s41374-018-0184-7. Epub 2019 Jan 24.
Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα.
成纤维样滑膜细胞（FLS）是类风湿关节炎（RA）关节炎症的主要贡献者。免疫细胞中的叉头框蛋白 O3（FOXO3）的改变与 RA 的发病机制越来越相关。在这里，我们表明，FOXO3 在类风湿关节炎滑膜的 FLS 中明显失活/磷酸化。在体外，肿瘤坏死因子-α（TNFα）刺激 FLS 可迅速并持续失活 FOXO3。mRNA 谱分析显示，FOXO3 的失活对于 TNFα 持续的促炎干扰素反应（CXCL9、CXCL10、CXCL11 和 TNFSF18）很重要。从机制上讲，我们的研究表明，FOXO3 的失活是由 TNF 诱导的磷酸肌醇 3-激酶相互作用蛋白 1（PIK3IP1）下调引起的。因此，我们确定 FOXO3 及其调节剂 PIK3IP1 是常驻间充质细胞对 TNFα 炎症反应的关键调节回路，并深入了解滑膜组织如何引发由 TNFα 驱动的慢性炎症。
