Epigenetic Regulatory Axis MIR22-TET3-MTRNR2L2 Represses Fibroblast-Like Synoviocyte-Mediated Inflammation in Rheumatoid Arthritis

Yilong Fang; Wei Huang; Xiangling Zhu; Xinming Wang; Xuming Wu; Huihui Wang; Wenming Hong; Shangxue Yan; Lingling Zhang; Yujie Deng; Wei Wei; Jiajie Tu; Chen Zhu

doi:10.1002/art.42795

Epigenetic Regulatory Axis MIR22-TET3-MTRNR2L2 Represses Fibroblast-Like Synoviocyte-Mediated Inflammation in Rheumatoid Arthritis

Arthritis Rheumatol. 2024 Jan 14. doi: 10.1002/art.42795. Online ahead of print.

Authors

Yilong Fang¹, Wei Huang², Xiangling Zhu¹, Xinming Wang³, Xuming Wu¹, Huihui Wang¹, Wenming Hong³, Shangxue Yan¹, Lingling Zhang¹, Yujie Deng⁴, Wei Wei¹, Jiajie Tu¹, Chen Zhu²

Affiliations

¹ Anhui Medical University and Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China.
² The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China.
³ The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁴ Guangzhou National Laboratory, Guangzhou, China.

PMID: 38221658
DOI: 10.1002/art.42795

Abstract

Objective: The specific role of fibroblast-like synoviocytes (FLSs) 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, microRNA (miRNA)-22 (MIR22), ten-eleven translocation methylcytosine dioxygenase 3 (TET3), and MT-RNR2 like 2 (MTRNR2L2), in RA-FLSs.

Methods: The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22^-/- and Tet3^+/- mice were used to establish a collagen antibody-induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen-induced (CIA) model. Bioinformatics, luciferase reporter assay, 5-hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation-qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2.

Results: The 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-FLSs by binding to its 3' untranslated region in TET3. The Tet3^+/- mice-established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA-FLSs.

Conclusion: The key role of the MIR22-TET3-MTRNR2L2 pathway in RA-FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs.

Abstract

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