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. 2023 Dec-Dec;22(23-24):2602-2621.
doi: 10.1080/15384101.2024.2302281. Epub 2024 Jan 16.

m6A-mediated lncRNA MAPKAPK5-AS1 induces apoptosis and suppresses inflammation via regulating miR-146a-3p/SIRT1/NF-κB axis in rheumatoid arthritis

Jianting Wen  1   2   3 , Jian Liu  1   2   4 , Lei Wan  1   2   4 , Hui Jiang  1   4 , Ling Xin  1   4 , Yue Sun  1   4 , Yanyan Fang  1   4 , Xin Wang  1   4 , Jie Wang  1   4
Affiliations

m6A-mediated lncRNA MAPKAPK5-AS1 induces apoptosis and suppresses inflammation via regulating miR-146a-3p/SIRT1/NF-κB axis in rheumatoid arthritis

Jianting Wen et al. Cell Cycle. 2023 Dec-Dec.

Abstract

To investigate the role of m6A-mediated lncRNA MAPKAPK5-AS1 (MK5-AS1) in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and its underlying molecular mechanism. RT-qPCR, western blot, flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA) were utilized for evaluating inflammation and apoptosis. Next, RIP, RNA pull-down, dual-luciferase reporter gene assay, and a series of rescue experiments were performed to explore the regulatory mechanisms of MK5-AS1 and its sponge-like action in RA-FLSs. The regulatory relationships between MK5-AS1 and WTAP were explored using the MeRIP-qPCR assay and RT-qPCR. Finally, the critical RNAs in the ceRNA axis were verified in the clinical cohort. MK5-AS1 was poorly expressed and miR-146a-3p was overexpressed in co-cultured RA-FLSs. MK5-AS1 overexpression could inhibit inflammatory responses and promote cell apoptosis in the co-cultured RA-FLSs. MK5-AS1 bound to miR-146a-3p to target SIRT1, thereby affecting inflammatory responses and cell apoptosis in the co-cultured RA-FLSs. SIRT1 knockdown or miR-146a-3p overexpression reversed the impacts of MK5-AS1 overexpression on co-cultured RA-FLSs inflammation and apoptosis. Moreover, WTAP was downregulated, and induced the inhibition of MK5-AS1 by promoting its RNA transcript stability. Clinically, MK5-AS1 was downregulated in RA-PBMCS and correlated with the clinical characteristics of RA. Our study elucidated that m6A-mediated MK5-AS1 sequestered miR-146a-3p to suppress SIRT1 expression in co-cultured RA-FLSs, thus providing a new insight into the treatment of rheumatoid arthritis.

Keywords: MAPKAPK5-AS1; Rheumatoid arthritis; apoptosis; ceRNA; inflammatory responses; m6A.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

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Grants and funding

This work was supported by grants from the Ministry of Science and Technology National Key Research and Development Program Chinese Medicine Modernization Research Key Project (2018YFC1705204); National Nature Fund Program (82274490, 81973655, 82074373); The University Synergy Innovation Program of Anhui Province (GXXT-2020-025); Open Foundation of Key Laboratory of Xin’an Medical Ministry of Anhui University of Traditional Chinese Medicine (No.2020×ayx10); Open Foundation of Anhui Province Key Laboratory of Modern Chinese Medicine Department of Internal Medicine Application Foundation Research and Development (2021AKLMCM004); Anhui Province Major and Intractable Diseases Collaborative Research Project of Traditional Chinese and Western Medicine (Anhui Traditional Chinese Medicine Development [2021] No. 70).

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