Silica-induced innate immune activation drives macrophage pyroptosis and lung inflammation through glycolytic reprogramming.

Prolonged inhalation of silica causes silicosis, characterized by persistent lung inflammation and irreversible fibrosis, but the mechanism has not been fully illuminated. In the present study, silicosis cases and healthy controls were employed to access the associations between Toll-like receptor 4 (TLR4) and silicosis risk. Silicosis mouse models and macrophage models were established to investigate whether the TLR4/NF-κB pathway drives pyroptosis through glycolytic reprogramming. The associations of TLR4 with glycolytic/pyroptosis markers, as well as its role in silicosis diagnosis, were further evaluated in the case-control population. TLR4 expression was significantly elevated in silicosis patients and positively associated with silicosis risk, with each unit increase in TLR4 linked to a 1.81-fold higher risk (95 % CI: 1.51, 2.23). TLR4 expressions were negatively and linearly associated with FEV/FVC, showing a -3.22 % increment (95 % CI: 5.21 %, -1.23 %) per logarithmic unit increase in TLR4 level. In experimental models, silica activated TLR4/NF-κB pathway, while inhibiting TLR4 activation notably alleviated macrophage pyroptosis and epithelial-mesenchymal transition (EMT) by reversing glycolytic reprogramming invitro. Additionally, TLR4 was positively associated with glycolytic and pyroptosis indicators in case-control population. The ROC curve analysis showed an area under the curve (AUC) of 0.77 (95 % CI: 0.71, 0.82) for TLR4. And the AUC for the combination of TLR4, plasma lactate, and lung function parameters reached 0.96 (95 % CI: 0.94, 0.98), significantly outperforming lung function alone. In conclusion, TLR4/NF-κB might drive silica-induced macrophage pyroptosis by triggering glycolytic reprogramming. And TLR4 hold potential as a biomarker for adjunctive diagnosis and early prevention of silicosis.