Inflammasome Independent Leukotriene B4 Production Drives Crystalline Silica Induced Sterile Inflammation in Lungs

Abstract

Abstract Occupational exposure to Crystalline Silica (CS) is a major public health concern with millions of workers continuously exposed to CS. Deposition of fine silica particles in the lungs can lead to severe lung inflammation and cancer. Lipid chemokine Leukotriene B4 (LTB4) and IL-1b that mediate leukocyte recruitment to the site of injury, are the key mediators of CS-induced sterile inflammation. Our previous studies have shown that CS exposure increases lung tumor burden in K-rasLA1 mice and that is abrogated in the LTB4 receptor, BLT1 deficient mice. Here, we show that phagocytosis of CS sequentially activates a series of pathways leading to LTB4, IL-1b and CXC chemokine production. CS uptake induces rapid formation of lipid bodies termed “lipidosome” independent of inflammasome activation. Studies with inhibitors suggested that CS-induced lipidosome formation and LTB4 production is linked to the phagocytosis pathway, an observation confirmed by confocal microscopy. We further demonstrated the SiRNA knockdown of cPla2, JNK or Rab40c prevents the formation of lipidosome and production of LTB4. Lastly, we demonstrate using an air pouch model in mice that JNK inhibitor, BI-78D3 is effective in reducing CS induced sterile-inflammation in-vivo. In summary, our studies highlight a novel inflammasome independent and JNK activation dependent lipidosome pathway leading to the production LTB4 as a major regulator of CS-induced sterile inflammation.