Cx3cr1 depletion ameliorates lipid metabolic dysregulation and pulmonary fibrosis induced by silica.

Abstract

Silicosis is characterized by pulmonary fibrosis, and there is currently no effective treatment available. The dysregulation of macrophage lipid metabolism is critical in the pathogenesis of pulmonary fibrosis, however, the underlying molecular mechanisms remain unclear. Here, we show that in silicosis murine model Cx3cr1 is a key gene of lung macrophage lipid metabolism and Cx3cr1 depletion ameliorates silica-induced pulmonary fibrosis probably by inhibiting lipid metabolic dysregulation. Firstly, the transcriptomic analysis of lung macrophages from a silicosis mouse model identified Cx3cr1 as a potentially key regulatory gene. Subsequently Cx3cr1macrophages were sorted by flow cytometry and integrative analyses, including Ingenuity Pathway Analysis (IPA), suggested that Cx3cr1 may promote silicosis fibrosis by perturbing lipid metabolism in lung macrophages. Single-cell RNA sequencing and pseudotime trajectory analysis in a mouse model of bleomycin-induced pulmonary fibrosis confirmed the role of Cx3cr1 in lung macrophage lipid metabolism. Cx3cr1 knockout in vivo leads to reduced lipid accumulation, decreased levels of pro-inflammatory and pro-fibrotic mediators, inhibition of pulmonary fibrosis induced by silica. In addition, Cx3cr1 knockout in RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were also established, and then the cells were stimulated with silica and oxidized low-density lipoprotein (ox-LDL). The results in vitro revealed that Cx3cr1 depletion ameliorates macrophage lipid metabolic dysregulation. Mendelian Randomization (MR) analysis also identified CX3CR1 as a risk factor for pneumoconiosis. Overall, these results suggest that targeted inhibition of Cx3cr1 may offer a potential therapeutic approach for correcting macrophage lipid metabolic dysregulation and attenuating silica-induced pulmonary fibrosis.