LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure.

Abstract

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 μM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-β1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.

• Authors: Tian Xiao, Zhonglan Zou, Junchao Xue, Binafsha Manzoor Syed, Jing Sun, Xiangyu Dai, Ming Shi, Junjie Li, Shaofeng Wei, Huanwen Tang, Aihua Zhang, Qizhan Liu
• Journal: Environmental pollution (Barking, Essex : 1987) (Environ Pollut) Vol. 268 Issue Pt A Pg. 115810 (Jan 01 2021) ISSN: 1873-6424 [Electronic] England
• PMID: 33162208 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• MicroRNAs
• RNA, Long Noncoding
• Arsenic

Topics

• Animals
• Arsenic (toxicity)
• Cell Differentiation
• Humans
• Macrophages
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics)
• Myofibroblasts
• Pulmonary Fibrosis (chemically induced)
• RNA, Long Noncoding (genetics)