Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 19, Issue -, Pages 350-360Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2019.11.018
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Funding
- National Natural Science Foundation of China [81972988]
- Natural Science Foundation of Hebei Province [H20162091705]
- Science and Technology Research Project of Hebei Province Universities [ZD2019077]
- Preeminence Youth Foundation of North China University of Science and Technology [JP201513]
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Silicosis is a fatal profession-related disease linked to long-term inhalation of silica. The present study aimed to determine whether meprin alpha, 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 macro-phages, primary lung fibro-blasts, and mouse embryonic fibroblasts were used to evaluate the expression and function of meprin alpha and miR-155-5p. In vitro meprin alpha manipulation was performed by recombinant mouse meprin alpha protein, actinonin (its inhibitor), and small interfering RNA knock-down. Macrophage and fibroblast activation was assessed by western blotting, real-time PCR, matrix deposition, and immunohistochemical staining. The roles of meprin alpha and miR-155-5p were also investigated in mice exposed to silica. We found that the meprin alpha level was stably repressed in silicotic rats. In vitro, silica decreased meprin alpha, and exogenous meprin alpha reduced activation of macrophages and fibroblasts induced by profibrotic factors. miR-155-5p negatively regulated Mepla by binding to the 3' untranslated region. Treatment with anti-miR-155-5p elevated meprin alpha, ameliorated macrophage and fibroblast activation, and attenuated lung fibrosis in mice induced by silica. The sustained repression of meprin alpha and beneficial effects of its rescue by inhibition of miR-155-5p during silicosis indicate that miR-155-5p/meprin alpha are two of the major regulators of silicosis.
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