miR‐21‐regulated M2 polarization of macrophage is involved in arsenicosis‐induced hepatic fibrosis through the activation of hepatic stellate cells

Abstract

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.

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

“…Taken together, miR-21 was determined as a fibrosis-associated miRNA, which could induce inflammation by activating IL-6 expression in LF tissue, resulting in LF fibrosis and hypertrophy. Like miR-221, accumulated studies have considered microRNA-21 as a central regulator of fibrotic diseases (e.g., hepatic fibrosis, skin fibrosis, and cardiac fibrosis) via various targets or molecular mechanism (e.g., inflammation, immunoreaction, and autophagy) (Yan et al, 2020;Sun et al, 2021;Xue et al, 2021). Thus, miR-21 as a potential diagnostic or therapeutic target for fibrosis diseases should be highlighted in future.…”

Snail-Regulated Exosomal MicroRNA-21 Suppresses NLRP3 Inflammasome Activity to Enhance Chemoresistance

“…However, tumoral miR-21 is inversely associated with the densities of CD3 + and CD45RO + cells in colorectal cancers 52 . Furthermore, miR-21 promotes M2 polarization 53 , and our previous work has shown that miR-21-containing TEXs are potent regulators of TAMs through the promotion of M2-like activation 7 . Here, we further revealed that miR-21-containing TEXs inhibited NLRP3 in ammasome activity.…”

Is Arsenic Exposure a Risk Factor for Metabolic Syndrome? A Review of the Potential Mechanisms

“…Kupffer cells are liver-residing macrophages that play important roles in developing of hepatic insulin resistance and fibrosis induced by diet ( 202 , 203 ). In vitro treatment of THP-1 derived macrophages with sodium arsenite (up to 8 µM for 48 h) promoted differentiation into M2 macrophages, inducing secretion of fibrogenic cytokines via upregulation of the miRNA miR-21 ( 204 ). This pathway correlated with the observation in the liver from C57BL6 mice exposed to 40 ppm of sodium arsenite for six months.…”