Wan Zhiping, Yang Xiaoan, Liu Xiaoquan, Sun Yinfang, Yu Piaojian, Xu Fen, Deng Hong
Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
Guangdong Provincial Key Laboratory of Diabetology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
iScience. 2022 Jun 14;25(7):104597. doi: 10.1016/j.isci.2022.104597. eCollection 2022 Jul 15.
Liver fibrosis is a severe stage of nonalcoholic fatty liver disease (NAFLD), which is closely associated with the activation of hepatic stellate cells (HSCs) and their interaction with macrophages. Exosomes can mediate crosstalk between macrophages and HSCs in NAFLD-associated fibrosis. We found that M2 macrophage-derived exosomes significantly inhibit HSCs activation. RNA-seq studies revealed that miRNA-411-5p was decreased in serum exosomes of nonalcoholic steatohepatitis (NASH) patients as compared with that in healthy controls. Besides, miR-411-5p and M2 macrophage markers are decreased in the liver of the NASH model. We further proved that exosomal miR-411-5p from M2 macrophages inhibit HSCs activation and miR-411-5p directly downregulated the expression of Calmodulin-Regulated Spectrin-Associated Protein 1 () to inactivate stellate cells. Importantly, knockdown of also inhibited HSCs activation. This study contributes to understanding the underlying mechanism of HSCs activation and indicates may serve as a potential therapeutic target for NASH.
肝纤维化是非酒精性脂肪性肝病（NAFLD）的严重阶段，与肝星状细胞（HSCs）的激活及其与巨噬细胞的相互作用密切相关。外泌体可介导NAFLD相关纤维化中巨噬细胞与HSCs之间的串扰。我们发现M2巨噬细胞衍生的外泌体显著抑制HSCs激活。RNA测序研究表明，与健康对照相比，非酒精性脂肪性肝炎（NASH）患者血清外泌体中的miRNA-411-5p减少。此外，NASH模型肝脏中miR-411-5p和M2巨噬细胞标志物减少。我们进一步证明，M2巨噬细胞的外泌体miR-411-5p抑制HSCs激活，且miR-411-5p直接下调钙调蛋白调节的血影蛋白相关蛋白1（）的表达以使星状细胞失活。重要的是，敲低也抑制HSCs激活。本研究有助于理解HSCs激活的潜在机制，并表明可能作为NASH的潜在治疗靶点。
