Epigenetic regulatory axis MIR22‐TET3‐MTRNR2L2 represses fibroblast‐like synoviocyte‐mediated inflammation in Rheumatoid Arthritis

Abstract

ObjectiveThe specific role of fibroblast‐like synoviocytes (FLS) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, MIR22, TET3, and MTRNR2L2, in RA‐FLS.MethodsThe expression of MIR22, TET3 and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by FISH, qPCR, IHC and western blot. Mir22‐/‐ and Tet3+/‐ mice were used to establish CAIA model. Mir22 angomir and Tet3 siRNA were used to illustrate the therapeutic effects on arthritis using CIA model. Bioinformatics, luciferase reporter assay, 5hmC dot blotting, ChIP‐qPCR and hMeDIP‐qPCR were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2.ResultsThe Mir22‐/‐ CAIA model and RA‐FLS‐related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA‐FLS by binding to its 3′UTR in TET3. The Tet3+/‐ mice‐established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the pro‐inflammatory effect of TET3 in RA. In addition, CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its pro‐inflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA‐FLS.ConclusionThe key role of the MIR22‐TET3‐MTRNR2L2 pathway in RA‐FLS provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLS.