Department of Laboratory Medicine, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, Guangdong, 528200, China.
The Department of Laboratory Medicine, Shunde Hospital, Southern Medical University, The First People's Hospital of Shunde Foshan, Foshan, Guangdong, China.
Mol Med. 2024 Nov 29;30(1):237. doi: 10.1186/s10020-024-01005-4.
Rheumatoid arthritis (RA) is a common autoimmune disease that can lead to irreversible joint damage when it occurs, but its pathogenesis has not yet been elucidated. In this study, we explored the roles of macrophage migration inhibitory factor (MIF), endoplasmic reticulum stress (ER stress), and Th17 cells in the pathogenesis of RA. We have preliminarily confirmed that MIF expression in CD4T cells and the proportion of Th17 cells are increased in active RA patients. We also found that ER stress is activated, initiating ATF6 pathway in the UPR. Additionally, using in vitro stimulation and co-immunoprecipitation experiments, we have confirmed the interaction between MIF and ATF6, which enhances protein expression in ATF6 pathway. Subsequently, in the chromatin immunoprecipitation assay, we observed the enrichment of ATF6 subunit on the promoter sequences of the Th17 cell differentiation genes STAT3 and RORC. Additionally, the differentiation of Th17 cells was disrupted by Ceapin-A7 (ATF6 inhibitor). In summary, our results indicate that MIF enhances ATF6 pathway signaling, which promotes the differentiation of Th17 cells. This could be a potential mechanism underlying the pathogenesis of RA, offering a new direction for the clinical treatment of RA.
类风湿关节炎（RA）是一种常见的自身免疫性疾病，在发生时可导致不可逆的关节损伤，但发病机制尚未阐明。在本研究中，我们探讨了巨噬细胞移动抑制因子（MIF）、内质网应激（ER 应激）和 Th17 细胞在 RA 发病机制中的作用。我们初步证实，活动期 RA 患者 CD4T 细胞中 MIF 的表达和 Th17 细胞的比例增加。我们还发现 ER 应激被激活，启动 UPR 中的 ATF6 途径。此外，通过体外刺激和共免疫沉淀实验，我们证实了 MIF 与 ATF6 的相互作用，这增强了 ATF6 途径中的蛋白表达。随后，在染色质免疫沉淀实验中，我们观察到 ATF6 亚基在 Th17 细胞分化基因 STAT3 和 RORC 的启动子序列上的富集。此外，Ceapin-A7（ATF6 抑制剂）破坏了 Th17 细胞的分化。总之，我们的结果表明，MIF 增强了 ATF6 途径信号，促进了 Th17 细胞的分化。这可能是 RA 发病机制的潜在机制，为 RA 的临床治疗提供了新的方向。
