MIF promotes Th17 cell differentiation in rheumatoid arthritis through ATF6 signal pathway

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 CD4⁺T 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.