Glycolysis alteration drives silica-induced NLRP3-dependent pyroptosis through promoting lactylation modification

Crystalline silica (CS) is a ubiquitous inhalable hazardous particle in natural and industrial activities. Prolonged inhalation of environmental CS can cause silicosis, characterized by persistent pulmonary inflammation and inreversible fibrosis, but the mechanism has not been elucidated. To uncover the role of aberrant glycolysis alteration in CS-induced NLRP3 activation and subsequent inflammatory response, we conducted this study by establishing mouse models and macrophage models. The results indicated that the CS-induced lung inflammation models were accompanied by glycolysis alteration, NLRP3 inflammasome activation, and pyroptosis. The application of glycolysis inhibitor (2-DG) suppressed CS-induced NLRP3 inflammasome activation, and alleviated lung inflammation. In the CS-induced macrophage activation models, 2-DG effectively impeded NLRP3 inflammasome activation and macrophage pyroptosis. Furtherly, aerobic glycolysis product, lactate could facilitate NLRP3 inflammasome activation and macrophage pyroptosis synergistically with CS particles. While blocking the source of lactate could largely alleviate CS-induced NLRP3 activation and macrophage pyroptosis. More profoundly, the increment of lactate induced by CS might promote NLRP3 inflammasome-dependent pyroptosis by increasing the levels of lactylation modifications. In conclusion, our findings demonstrated aberrant glycolysis could facilitate CS-induced NLRP3 inflammasome activation, macrophage pyroptosis, and inflammatory response. Increased glycolytic product lactate may play a key role in NLRP3-dependent pyroptosis through protein lactylation modifications.