Macrophage-Derived miR-100-5p Orchestrates Synovial Proliferation and Inflammation in Rheumatoid Arthritis through mTOR Signaling

Author:

Liu Huan1,Chen Yuehong1,Huang Yupeng1,Wei Ling2,Ran Jingjing1,Li Qianwei1,Tian Yunru1,Luo Zhongling1,Yang Leiyi1,Liu Hongjiang1,Yin Geng1,Xie Qibing1

Affiliation:

1. West China Hospital of Sichuan University

2. Hospital of Chengdu Office of People’s Government of Tibetan Autonomous region

Abstract

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, causing substantial disability and reducing life quality. While macrophages are widely appreciated as a master regulator in the inflammatory response of RA, the precise mechanisms underlying the regulation of proliferation and inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS) remain elusive. Here, we provide extensive evidence to demonstrate that macrophage contributes to RA microenvironment remodeling by extracellular vesicles (sEVs) and downstream miR-100-5p/ mammalian target of rapamycin (mTOR) axis. Results We showed that cBMDM-sEVs exhibited a notable increase in abundance compared with nBMDM-sEVs. cBMDM-sEVs induced significant RA-FLS proliferation and potent inflammatory responses. Mechanistically, decreased levels of miR-100-5p were detected in cBMDM-sEVs compared with nBMDM-sEVs. miR-100-5p overexpression ameliorated RA-FLS proliferation and inflammation by targeting the mTOR pathway. Partial attenuation of the inflammatory effects induced by cBMDM-sEVs on RA-FLS was achieved through the introduction of an overexpression of miR-100-5p. Conclusions Our work reveals the critical role of macrophages in exacerbating RA by facilitating the transfer of miR-100-5p-deficient sEVs to RA-FLS, and sheds light on novel disease mechanisms and provides potential therapeutic targets for RA interventions.

Publisher

Research Square Platform LLC

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