The NLRP3/ASC/Caspase‐1 axis regulates IL‐1β processing in neutrophils

Abstract

Neutrophils play a pivotal role in the defense against bacterial, viral and fungal infections and are important mediators in the acute inflammatory response. At the same time, neutrophils are also in volved in sterile inflammatory responses that are triggered by endogenous ligands. A series of immediate effector functions and the expression of proinflammatory genes enable neutrophils to initiate the immune response against the injurious agent. Among these, interleukin‐1β (IL‐1β) plays a key role in the orchestration of the inflammatory response. Induction of IL‐1β expression leads to production of cytosolic pro‐IL‐1β, which requires further processing by a proteolytic cleavage event. Caspase‐1 was initially identified as the main IL‐1β‐converting enzyme, and the upstream events leading to caspase‐1 activation were identified as so‐called inflammasome complexes. Up to now, the inflammasome system has mainly been studied in macrophages, whereas the inflammasome was thought to play a redundant or no role in the cell intrinsic processing of pro‐IL‐1β in neutrophils. Here, we identify the expression of the components of the NLRP3 inflammasome complex in neutrophils and show that the NLRP3 inflammasome pathway is indeed operational in neutrophils. Our findings establish the NLRP3 inflammasome as a key step in the secretion of matured IL‐1β by neutrophils.