Shu Bo, Zhang Rui-Zhi, Zhou Ying-Xia, He Chao, Yang Xin
Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, PR China.
Department of Surgical Operation, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, PR China.
Cell Death Discov. 2022 May 19;8(1):266. doi: 10.1038/s41420-022-01036-y.
Hepatic fibrosis (HF) is caused by chronic hepatic injury and is characterized by hepatic stellate cells (HSCs) activation. Studies focusing on the function of exosomes derived from macrophages in HF progression are limited. This study aims to identify the roles of exosomal NEAT1 derived from macrophages on HF and the underlying mechanisms. Our studies showed that METTL3 targeted and enhanced NEAT1 expression in macrophages. Exosomal NEAT1 originating from LPS-treated macrophages promoted HSCs proliferation and migration, and induced the expression of fibrotic proteins including collagen I, α-SMA, and fibronectin. Macrophage exosomal NEAT1 contributed to HSCs activation by sponging miR-342. MiR-342 directly targeted Sp1 and suppressed its downstream TGF-β1/Smad signaling pathway, which eventually led to the inhibition of HSCs activation. Depletion of NEAT1 in the macrophage exosomes inhibited HF progression both in vitro and in vivo. Altogether, our study proved that silence of NEAT1 in the macrophage exosomes exerted protective roles against HF through the miR-342/Sp1/TGF-β1/Smad signaling pathway, suggesting a potential therapeutic target in HF treatment.
肝纤维化（HF）由慢性肝损伤引起，其特征是肝星状细胞（HSCs）活化。关于巨噬细胞来源的外泌体在HF进展中的功能的研究有限。本研究旨在确定巨噬细胞来源的外泌体NEAT1在HF中的作用及其潜在机制。我们的研究表明，METTL3靶向并增强巨噬细胞中NEAT1的表达。源自脂多糖处理的巨噬细胞的外泌体NEAT1促进HSCs增殖和迁移，并诱导包括I型胶原、α-平滑肌肌动蛋白和纤连蛋白在内的纤维化蛋白的表达。巨噬细胞外泌体NEAT1通过结合miR-342促进HSCs活化。miR-342直接靶向Sp1并抑制其下游TGF-β1/Smad信号通路，最终导致HSCs活化受到抑制。巨噬细胞外泌体中NEAT1的缺失在体外和体内均抑制HF进展。总之，我们的研究证明，巨噬细胞外泌体中NEAT1的沉默通过miR-342/Sp1/TGF-β1/Smad信号通路对HF发挥保护作用，提示其可能是HF治疗的潜在靶点。
