Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Mice by Regulating Meprin α

Yingying Chen; Dingjie Xu; Jingxin Yao; Zhongqiu Wei; Shifeng Li; Xuemin Gao; Wenchen Cai; Na Mao; Fuyu Jin; Yaqian Li; Ying Zhu; Shumin Li; Heliang Liu; Fang Yang; Hong Xu

doi:10.1016/j.omtn.2019.11.018

Inhibition of miR-155-5p Exerts Anti-Fibrotic Effects in Silicotic Mice by Regulating Meprin α

Mol Ther Nucleic Acids. 2020 Mar 6:19:350-360. doi: 10.1016/j.omtn.2019.11.018. Epub 2019 Nov 26.

Authors

Yingying Chen¹, Dingjie Xu², Jingxin Yao¹, Zhongqiu Wei³, Shifeng Li¹, Xuemin Gao¹, Wenchen Cai⁴, Na Mao⁴, Fuyu Jin¹, Yaqian Li¹, Ying Zhu¹, Shumin Li⁴, Heliang Liu⁵, Fang Yang⁵, Hong Xu⁶

Affiliations

¹ Medical Research Center, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China.
² Traditional Chinese Medicine College, North China University of Science and Technology, Tangshan, Hebei 063210, China.
³ Basic Medical College, North China University of Science and Technology, Tangshan, Hebei 063210, China.
⁴ School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China.
⁵ Medical Research Center, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China; School of Public Health, North China University of Science and Technology, Tangshan, Hebei 063210, China.
⁶ Medical Research Center, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, Hebei 063210, China. Electronic address: xuhong@ncst.edu.cn.

Abstract

Silicosis is a fatal profession-related disease linked to long-term inhalation of silica. The present study aimed to determine whether meprin α, a master regulator of anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), is diminished by miR-155-5p in silicotic and control lung macrophages and fibroblasts upon activation. NR8383 macrophages, primary lung fibroblasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin α and miR-155-5p. In vitro meprin α manipulation was performed by recombinant mouse meprin α protein, actinonin (its inhibitor), and small interfering RNA knockdown. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin α and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin α level was stably repressed in silicotic rats. In vitro, silica decreased meprin α, and exogenous meprin α reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mep1a by binding to the 3' untranslated region. Treatment with anti-miR-155-5p elevated meprin α, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin α and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin α are two of the major regulators of silicosis.

Keywords: fibroblast; macrophage; meprin; miRNA-155-5p; silicosis.