miR-21-regulated M2 polarization of macrophage is involved in arsenicosis‐induced hepatic fibrosis through the activation of hepatic stellate cells.
miR-21-regulated M2 polarization of macrophage is involved in arsenicosis‐induced hepatic fibrosis through the activation of hepatic stellate cells.
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miR-21 调节的巨噬细胞 M2 极化参与砷中毒通过肝星状细胞的激活诱导的肝纤维化。
DOI：
10.1002/jcp.30288
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发表时间：
2021
影响因子：
5.6
通讯作者：
Qizhan Liu
中科院分区：
文献类型：
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作者：
Junxue Chao;Tian Xiao;Shaofeng Wei;Jing Sun;Zhonglan Zou;Ming Shi;Qian Sun;Xiangyu Dai;Lu Wu;Junjie Li;Haibo Xia;Huanwen Tang;Aihua Zhang;Qizhan Liu
慢性砷中毒是公认的危害公众健康的主要因素之一。砷暴露可引起肝纤维化，但其发生的分子机制是复杂和难以捉摸的。目前尚不清楚miRNAs是否参与砷诱导的肝纤维化。我们发现，在暴露于亚砷酸盐的小鼠肝脏中，microRNA-21水平升高。(miR-21），磷酸化的哺乳动物雷帕霉素靶蛋白（p-mTOR），和磷酸化酶1（Arg 1）;低水平的磷酸酶和张力蛋白同源物（PTEN）;和更广泛的肝纤维化。对于培养的细胞，亚砷酸盐诱导miR-21、p-mTOR和Arg 1;减少PTEN;并促进THP-1单核细胞（THP-M）衍生的巨噬细胞的M2极化，这导致纤维化细胞因子（包括转化生长因子-β1）的分泌。亚砷酸盐处理的THP‐M与LX‐ 2.细胞的共培养诱导LX‐2细胞中的α‐SMA和胶原I，并导致这些细胞的活化。THP-M中miR-21的下调抑制了亚砷酸盐诱导的M2.极化和LX-2细胞的活化，但与PTEN siRNA或miR-21抑制剂共转染逆转了这种抑制。此外，与暴露于亚砷酸盐的WT小鼠相比，小鼠中miR-21的敲除减轻了肝纤维化和M2极化。此外，在砷水平较高的患者中，LN、PCIII和HA水平较高，并且miR-21水平高于对照组，并且与PCIII、LN和HA水平呈正相关。higher.hair因此，亚砷酸盐通过miR-21调节PTEN诱导巨噬细胞的M2极化，这参与了肝星状细胞的活化和肝纤维化。结果建立了一个以前未知的砷中毒诱导纤维化的机制。
Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main.damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis,.but the molecular mechanisms by which this occurs are complex and elusive. It is.not known if miRNAs are involved in arsenic‐induced liver fibrosis. We found that in.the livers of mice exposed to arsenite, there were elevated levels of microRNA‐21.(miR‐21), phosphorylated mammalian target of rapamycin (p‐mTOR), and arginase.1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive.liver fibrosis. For cultured cells, arsenite‐induced miR‐21, p‐mTOR, and Arg1; decreased.PTEN; and promoted M2 polarization of macrophages derived from THP‐1.monocytes (THP‐M), which caused secretion of fibrogenic cytokines, including.transforming growth factor‐β1. Coculture of arsenite‐treated, THP‐M with LX‐2.cells induced α‐SMA and collagen I in the LX‐2 cells and resulted in the activation of.these cells. Downregulation of miR‐21 in THP‐M inhibited arsenite‐induced M2.polarization and activation of LX‐2 cells, but cotransfection with PTEN siRNA or a.miR‐21 inhibitor reversed this inhibition. Moreover, knockout of miR‐21 in mice.attenuated liver fibrosis and M2 polarization compared with WT mice exposed to.arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher.hair arsenic levels, and levels of miR‐21 were higher than controls and positively.correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization.of macrophages via miR‐21 regulation of PTEN, which is involved in the activation of.hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown.mechanism for arsenicosis‐induced fibrosis.