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 proinflammatory cytokine production (e.g., interleukin-1β [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 among 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 proinflammatory and antimicrobial responses during pathogen challenge.

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

“…In B cells infected with Salmonella Typhimurium ΔsopB , we observed re-establishment of IL-Iβ secretion; surprisingly, these cells did not undergo pyroptosis (Figure S8). A similar event has been observed in neutrophils and primary human monocytes infected with Salmonella ; these cells secreted IL-1β without undergoing pyroptosis [6,50]. These results support the idea that IL-1β secretion might be a pyroptosis-independent mechanism.…”

“…In addition to macrophages, other cells of the immune system are targets of this pathogen, including dendritic cells and neutrophils [6,7]. Furthermore, we and others have reported that B cells are also a target of Salmonella [8–12].…”

Burn the house, save the day: pyroptosis in pathogen restriction

“…Gram-negative Salmonella spp, which cause typhoid fever and gastroenteritis, is one such example of an intracellular bacterium. Several studies have demonstrated clear functions for inflammasomes in controlling the replication of Salmonella, through cytokine activation and induction of pyroptosis [16,23,24].…”

“…Pyroptosis of infected cells is emerging as an important mechanism of microbial clearance [24], in addition to host defence mechanisms coordinated by inflammasomedependent IL-1β [16], and IL-18 [23,25]. Macrophage pyroptosis releases Salmonella from its intracellular replicative niche, and increases its susceptibility to neutrophil-mediated extracellular destruction (Figure 1).…”

“…While the molecular events directing pyroptosis execution downstream of caspase-1 activation are currently unknown, it is widely believed that this process involves proteolytic activation of specific pyroptotic death effector molecules, akin to the pathways controlling apoptosis. We recently reported that caspase-1 activation in neutrophils selectively triggers cytokine processing without concomitant cell death, suggesting that individual cell types may suppress the availability of pyroptotic death effectors as a means to modulate cell viability at a site of challenge [16].…”