Resistance to silicosis progression in mice with Ch25h downregulation: The involvement of NLRP3 inflammasome.

Abstract

Silicosis is a fatal occupational lung disease characterized by persistent inflammation and irreversible fibrosis. However, the pathogenesis of silicosis is currently unclear. In this study, a mouse model of silicosis was established by intranasal instillation of silica, and transcriptomic alterations in lung tissues were assessed by mRNA-sequencing. Cholesterol 25-hydroxylase (Ch25h) was upregulated in silicotic lung tissues and alveolar macrophages. Lentivirus-mediated Ch25h knockdown was then employed to assess its functional role in vivo. It was found that Ch25h knockdown alleviated associated pathological changes, including pulmonary injury and fibrosis. Additionally, Ch25h significantly modulated NLRP3 inflammasome activity in vivo and in vitro. Knockdown of Ch25h inhibited the secretion of inflammatory factor (IL-1α, IL-1β, and IL-18), decreased the protein level of cleaved caspase-1 and GSDMD-N in macrophages, and reduced potassium ion efflux and lactate dehydrogenase (LDH) release. Notably, ASC (apoptosis-related spotted protein) oligomerization was suppressed by Ch25h downregulation, suggesting that Ch25h was required for the inflammasome assembly. Our findings suggest that Ch25h may contribute to silicosis development by regulating NLRP3 inflammasome activation and pyroptosis, warranting further investigation as a possible therapeutic target.