Inflammasome-Independent Leukotriene B₄ Production Drives Crystalline Silica-Induced Sterile Inflammation

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B₄ (LTB₄) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB₄ and IL-1β in mouse macrophages, mast cells, and neutrophils. Phagosomes enclosing CS particles trigger the assembly of lipidosome in the cytoplasm, which is likely the primary source of CS-induced LTB₄ production. Activation of the JNK pathway is essential for both CS-induced LTB₄ and IL-1β production. Studies with bafilomycin-A1- and NLRP3-deficient mice revealed that LTB₄ synthesis in the lipidosome is independent of inflammasome activation. Small interfering RNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB₄ production. BI-78D3, a JNK inhibitor, abrogated CS-induced neutrophilic inflammation in vivo in an air pouch model. These results highlight an inflammasome-independent and JNK activation-dependent lipidosome pathway as a regulator of LTB₄ synthesis and CS-induced sterile inflammation.