Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

Summary Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin‐family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non‐classical secretion of IL‐1 family cytokines that amplify host‐beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL‐1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase‐1 to generate GSDMD macropores that mediate IL‐1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL‐1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase‐1‐mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD‐dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD‐dependent mechanisms for export of bioactive IL‐1β. Rather, neutrophils employ cell‐specific mechanisms to conditionally engage GSDMD‐mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.