IL33-regulated NPM1 promotes fibroblast-to-myofibroblast transition via ERK/AP-1 signaling in silica-induced pulmonary fibrosis

Abstract

Abstract Background: Silicosis is a global occupational lung disease caused by the accumulation of silica dust. There is a lack of effective clinical drugs, and the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms by which IL33 involves in silicosis progression need further exploration. Results: Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin (BLM) and silica treatment. ChIP assay, knockdown and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or co-cultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. Also, Treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. Conclusions: In this study, we identified that NPM1 could involve in the progression of silicosis, which was regulated by IL33/ERK/AP-1 signaling. And treatment methods targeting this pathway may provide new anti-fibrotic clues in pulmonary fibrosis.