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

Abstract

Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B (LTB) 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 LTB 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 LTB production. Activation of the JNK pathway is essential for both CS-induced LTB and IL-1β production. Studies with bafilomycin-A1- and NLRP3-deficient mice revealed that LTB 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 LTB 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 LTB synthesis and CS-induced sterile inflammation.

Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach

“…Individually, YpkA, YopE, YopH, YopJ, and YopT all appear to be sufficient to inhibit LTB 4 synthesis. Synthesis of LTB 4 requires activation and relocalization of the enzyme 5-lipooxygenase (5-LO) to a membrane such as the nucleus or endoplasmic reticulum or to recently described cytosolic structures called lipidosomes (23,104,105). In this active state, 5-LO rapidly converts arachidonic acid to LTA 4 , which is followed by conversion to LTB 4 by LTA 4 hydrolase (23,106).…”

Inflammatory and oxidative stress biomarkers induced by silica exposure in crystal craftsmen

“…Further longitudinal studies are needed to better understand the relationship between the types and levels of plasma biomarkers and compromised pulmonary status during silicosis as well as other silica‐related diseases. The identification of silica‐induced molecular targets from genes involved in oxidative stress, in inflammation and in mechanisms of pulmonary toxicity may contribute to knowledge that can lead to the development of earlier clinical and occupational interventions in the prevention of silicosis and other silica‐related diseases and even future treatment options 15,61 . The use of biomarkers, together with more sensitive imaging methods, may allow the design of algorithms that can be implemented to benefit early diagnosis of silicosis.…”

“…The inflammatory response has been described as essential to the pathogenesis of silicosis, both in human studies and in experimental animal models. The activation and recruitment of macrophages and neutrophils into the lung parenchyma, particularly on the NALP‐3 inflammasome, drives the production of inflammatory cytokines and chemokines, thus promoting and intensifying local tissue damage that culminates in collagen and elastin deposition and lung remodeling 11–15 . Among those mediators implicated in the pathogenesis of silicosis, the interleukins IL‐1β, IL‐4, IL‐5, IL‐6, IL‐8, and IL‐10 12,16–18 ; tumor necrosis factor (TNF) and its receptor sTNFR1 and sTNFR2; transforming growth factor β (TGF‐β), and the chemokines CCL3 and CCL24 have been highlighted 19,20 .…”

A guide to crystal‐related and nano‐ or microparticle‐related tissue responses

“…In addition, calcium oxalate crystals induce autophagy, as evident from increased expression of light chain 3‐II and beclin‐1 and the presence of autophagy‐related vacuoles . Crystalline silica particles inside the phagosome trigger the assembly of liposomes in the cytoplasm, which leads to the production of leukotriene B4 in an inflammasome‐independent manner .…”