PD-L1 upregulation in activated fibroblasts promotes silica particle-induced pulmonary fibrosis.

Silicosis is a severe interstitial lung disease resulting from prolonged exposure to silica dust in working environment, characterized by inflammation and fibrosis. This condition is closely associated with immune dysregulation, although the precise regulatory mechanisms remain elusive. Immune checkpoints (ICs) comprise receptor-ligand pairs crucial for immune cell activation and coordination of immune responses. Among these, PD-1 and its ligand PD-L1 have garnered significant attention in tumor research and have recently been implicated in the regulation of fibrotic diseases. Nonetheless, their involvement in silicosis remains unexplored. In this study, we observed a global upregulation of PD-1 and PD-L1 expression concomitant with the progression of silicosis, exhibiting cell specificity. Targeting PD-1/PD-L1 signaling mitigated silicosis in mice by modulating T cell homeostasis, macrophage polarization, and activation of fibrotic effector cells. Notably, PD-L1 expression on activated fibroblasts emerged as a pivotal driver of silicosis progression. Mechanistically, elevated PD-L1 levels in fibroblast activation fostered a positive feedback loop by binding to p-Smad2/3 and p-STAT3 proteins, thereby facilitating their nuclear translocation and augmenting protein stability, ultimately promoting fibroblast transdifferentiation. Consistently, knockdown of PD-L1 in lung fibroblasts significantly ameliorated silicosis in mice. In summary, PD-1/PD-L1 signaling mediates critical profibrotic signals during the progression of silicosis.