NLRP3 activation in neutrophils induces lethal autoinflammation, liver inflammation, and fibrosis

Sterile inflammation is a central element in liver diseases. The immune response following injurious stimuli involves hepatic infiltration of neutrophils and monocytes. Neutrophils are major effectors of liver inflammation, rapidly recruited to sites of inflammation, and can augment the recruitment of other leukocytes. The NLRP3 inflammasome has been increasingly implicated in severe liver inflammation, fibrosis, and cell death. In this study, the role of NLRP3 activation in neutrophils during liver inflammation and fibrosis was investigated. Mouse models with neutrophil‐specific expression of mutant NLRP3 were developed. Mutant mice develop severe liver inflammation and lethal autoinflammation phenocopying mice with a systemic expression of mutant NLRP3. NLRP3 activation in neutrophils leads to a pro‐inflammatory cytokine and chemokine profile in the liver, infiltration by neutrophils and macrophages, and an increase in cell death. Furthermore, mutant mice develop liver fibrosis associated with increased expression of pro‐fibrogenic genes. Taken together, the present work demonstrates how neutrophils, driven by the NLRP3 inflammasome, coordinate other inflammatory myeloid cells in the liver, and propagate the inflammatory response in the context of inflammation‐driven fibrosis. Synopsis Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis. Neutrophil‐specific NLRP3 activation leads to liver inflammation and lethal autoinflammation. NLRP3 activation in neutrophils induces pro‐inflammatory cytokine and chemokine profiles in the liver. NLRP3 activation in neutrophils leads to liver infiltration by neutrophils and macrophages, and an increase in cell death. Neutrophil‐specific NLRP3 activation results in liver fibrosis associated with increased expression of pro‐fibrogenic genes. Graphical Abstract Sterile inflammation is central to many liver diseases. This work shows how neutrophils coordinate other inflammatory myeloid cells in the liver and propagate the inflammatory response in the context of inflammation‐driven fibrosis.