Targeting CX3CR1 inhibits silica-induced epithelial-mesenchymal transition and pulmonary fibrosis in mice via the NF-κB signaling pathway.

Abstract

Silicosis is the most severe occupational disease, with complex fibrotic mechanisms and a lack of effective therapies. Macrophage CX3CR1 has recently been found to play an important role in fibrosis diseases, and our previous studies have revealed that silica induced epithelial-mesenchymal transition (EMT) via macrophages and EMT was closely related to silicosis fibrosis. However, whether macrophage CX3CR1 is involved in silica-induced EMT and pulmonary fibrosis remains unclear. This study aimed to clarify the role and mechanism of macrophage CX3CR1 in silica-induced EMT and pulmonary fibrosis. A silicosis model was established in two types of transgenic mice (Cx3cr1-knockout and Sftpc-EGFP mice), and CX3CR1 was inhibited via gene knockout and pharmacological intervention. Results showed that silica up-regulated CX3CR1 and induced EMT in alveolar epithelial cells while inhibiting CX3CR1 significantly alleviated EMT and fibrosis. In vitro two types of Cx3cr1 siRNA were used in RAW264.7 cells, and it showed that targeting CX3CR1 suppressed silica-induced EMT in MLE-12 cells. Transcriptomic analysis revealed enrichment of the NF-κB pathway in vivo. In vitro experiments further confirmed that combined inhibition of CX3CR1 and NF-κB synergistically alleviated silica-induced EMT. These findings indicate that the CX3CR1-NF-κB axis plays an important role in silica-induced EMT and pulmonary fibrosis, and targeting CX3CR1 inhibits silica-induced epithelial-mesenchymal transition and pulmonary fibrosis in mice via the NF-κB signaling pathway, providing new insights for the prevention and treatment of silicosis.