C3a-C3ar1 axis mediates macrophage M1 polarization to drive silicosis inflammation and fibrosis

Exposure to crystalline silica (CS) causes silicosis, characterized by chronic inflammation and progressive fibrosis. Imbalance in regulation between innate and adaptive immunity has been identified as a key immune mechanism underlying silicosis. However, the role and mechanism of complement system, a crucial component of innate immunity, in silicosis progression remain unclear. Here, through time-series transcriptome analysis, we systematically investigated the expression patterns of all complement components at different stages of silicosis. Notably, C3a-C3ar1 axis emerged as the only complement pathway consistently involved throughout silicosis development. Early inhibition of C3ar1 in inflammation has a good inhibitory effect on silicosis. In clinical samples, data indicated that C3a is highly expressed in the peripheral blood of patients with silicosis at different stages. And persistent depletion of C3 in bronchoalveolar lavage fluid cells supports the continuous production of C3a. Mechanistically, combining time-series single-cell sequencing, we identified that C3ar1 is localized in M1 macrophages. Inhibition of C3ar1 reduces macrophages recruitment and M1-type polarization through Ccl2-Ccr2 signaling pathway, thereby slowing down silicosis process. In summary, our findings highlight the importance of complement receptor C3ar1 in macrophage recruitment and polarization, identify complement C3a as a potential biomarker for auxiliary diagnosis and early prevention of silicosis, and provide new approaches and strategies for immunotherapy of silicosis.