Epithelial NLRP3 drives silica-induced lung injury and fibrosis through IL-18 and pro-fibrotic neutrophil recruitment.

BACKGROUND: Silicosis is a progressive inflammatory and fibrotic lung disease with no effective treatments beyond symptom management. While global NLRP3 inflammasome deficiency attenuates silica-induced pathology, myeloid-specific Nlrp3 deletion provides no protection, suggesting that other cellular sources drive disease. Given that epithelial cells directly encounter inhaled silica particles and express NLRP3, we investigated the functional contribution of epithelial Nlrp3 to silicosis pathogenesis. RESULTS: neutrophils and broadly reduced airway inflammatory cytokines, accompanied by decreased lung damage, alveolitis, collagen deposition, fibrotic nodule expansion, and α-SMA expression, independent of detectable TGFβ changes. By day 28, during the chronic fibrotic phase, alveolar epithelial Nlrp3 deficiency continued to confer protection, reducing persistent inflammation, collagen accumulation, and fibrotic nodule size. In parallel, deletion of Nlrp3 in Scgb1a1⁺ bronchiolar epithelial cells reduced early inflammasome activation at day 3 and similarly decreased chronic lung inflammation, collagen deposition, and fibrotic nodule expansion, without affecting nodule number or cellularity at day 28. CONCLUSIONS: These findings establish epithelial Nlrp3 as a critical driver of silica-induced fibrotic remodeling through IL-18 and pro-fibrotic neutrophil recruitment, independent of canonical TGFβ mechanisms. This epithelial-centric paradigm provides a rationale for precision therapeutic strategies targeting epithelial NLRP3.