165: The neutrophil NLRC4 inflammasome selectively promotes IL-1β maturation without pyroptosis during acute Salmonella challenge

Abstract

The macrophage NLRC4 inflammasome drives potent innate immune responses against Salmonella , by eliciting caspase-1-dependent pro-inflammatory cytokine production (e.g. interleukin (IL)-1β) and pyroptotic cell death. However, the potential contribution of other cell types to inflammasome-mediated host defense against Salmonella was unclear. Here we demonstrate that neutrophils, typically viewed as cellular targets of IL-1β, themselves activate the NLRC4 inflammasome during acute Salmonella infection, and are a major cell compartment for IL-1β production during acute peritoneal challenge in vivo . Importantly, unlike macrophages, neutrophils do not undergo pyroptosis upon NLRC4 inflammasome activation. The resistance of neutrophils to pyroptotic death is unique amongst inflammasome-signaling cells so far described, and allows neutrophils to sustain IL-1β production at a site of infection, without compromising the crucial inflammasome-independent antimicrobial effector functions that would be lost if neutrophils rapidly lysed upon caspase-1 activation. Inflammasome pathway modification in neutrophils thus maximizes host pro-inflammatory and antimicrobial responses during pathogen challenge. Cell Reports (in press).