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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\u2010induced liver fibrosis. We found that\u00a0in the livers of mice exposed to arsenite, there were elevated levels of microRNA\u201021 (miR\u201021), phosphorylated mammalian target of rapamycin (p\u2010mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite\u2010induced miR\u201021, p\u2010mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP\u20101 monocytes (THP\u2010M), which caused secretion of fibrogenic cytokines, including transforming growth factor\u2010\u03b21. Coculture of arsenite\u2010treated, THP\u2010M with LX\u20102 cells induced \u03b1\u2010SMA and collagen I in the LX\u20102 cells and resulted in the activation of these cells. Downregulation of miR\u201021 in THP\u2010M inhibited arsenite\u2010induced M2 polarization and activation of LX\u20102 cells, but cotransfection with PTEN siRNA or a miR\u201021 inhibitor reversed this inhibition. Moreover, knockout of <jats:italic>miR\u201021<\/jats:italic> in mice attenuated\u00a0liver 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\u201021 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR\u201021 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\u2010induced fibrosis.<\/jats:p>","DOI":"10.1002\/jcp.30288","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T04:07:55Z","timestamp":1611374875000},"page":"6025-6041","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["miR\u201021\u2010regulated M2 polarization of macrophage is involved in arsenicosis\u2010induced hepatic fibrosis through the activation of hepatic stellate cells"],"prefix":"10.1002","volume":"236","author":[{"given":"Junchao","family":"Xue","sequence":"first","affiliation":[{"name":"Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health Nanjing Medical University  Nanjing Jiangsu China"},{"name":"Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School 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