Liu Huan, Chen Yuehong, Huang Yupeng, Wei Ling, Ran Jingjing, Li Qianwei, Tian Yunru, Luo Zhongling, Yang Leiyi, Liu Hongjiang, Yin Geng, Xie Qibing
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Department of General Practice, West China Hospital, General Practice Medical Center, Sichuan University, Chengdu, 610041, China.
J Nanobiotechnology. 2024 Apr 22;22(1):197. doi: 10.1186/s12951-024-02444-1.
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.
We showed that bone marrow derived macrophage (BMDM) derived-sEVs (BMDM-sEVs) from collagen-induced arthritis (CIA) mice (cBMDM-sEVs) exhibited a notable increase in abundance compared with BMDM-sEVs from normal mice (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.
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.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为滑膜炎症，会导致严重残疾并降低生活质量。虽然巨噬细胞被广泛认为是RA炎症反应的主要调节因子，但RA来源的成纤维样滑膜细胞（RA-FLS）增殖和炎症调节的精确机制仍不清楚。在此，我们提供了大量证据证明巨噬细胞通过细胞外囊泡（sEVs）和下游miR-100-5p/雷帕霉素哺乳动物靶蛋白（mTOR）轴促进RA微环境重塑。
我们发现，与正常小鼠的骨髓来源巨噬细胞（BMDM）衍生的sEVs（nBMDM-sEVs）相比，胶原诱导性关节炎（CIA）小鼠的BMDM衍生的sEVs（cBMDM-sEVs）丰度显著增加。cBMDM-sEVs诱导RA-FLS显著增殖和强烈的炎症反应。机制上，与nBMDM-sEVs相比，cBMDM-sEVs中miR-100-5p水平降低。miR-100-5p过表达通过靶向mTOR途径改善RA-FLS增殖和炎症。通过引入miR-100-5p过表达，部分减弱了cBMDM-sEVs对RA-FLS诱导的炎症作用。
我们的研究揭示了巨噬细胞通过促进miR-100-5p缺陷的sEVs向RA-FLS转移在加重RA中的关键作用，阐明了新的疾病机制，并为RA干预提供了潜在的治疗靶点。
