Immune antigen-presenting cells and skin and mucosal epithelia vigorously respond to invasive microbial infection. When NOD-like receptors (NLRs) or AIM2-like receptors (ALRs) in the immune cell cytosol sense microbial products, they assemble the canonical inflammasome, which activates caspase-1 (initially called ICE).1 Caspases-4/5 in humans and caspase-11 in mice, expressed by immune cells and epithelial barrier cells, directly sense cytosolic lipopolysaccharide (LPS) from Gram− bacterial cell walls.2 These caspases are directly activated in an LPS–inflammatory caspase complex (the noncanonical inflammasome).3, 4 Inflammatory caspase activation causes a ‘fiery’ death, pyroptosis, that is morphologically and functionally distinct from apoptosis or necroptosis.5, 6 Caspase-1, but not other inflammatory caspases, also process and cause release of inflammatory cytokines (including IL-1β, IL-18) that cause fever. Triggering the noncanonical inflammasome indirectly activates the canonical inflammasome.3

Inflammasome activation protects against invasive pathogens by recruiting immune cells to infection sites and expelling microbes from favorable intracellular niches that promote their replication.7 However, this protective response causes sepsis—a vascular leak, multi-organ failure syndrome—if the infection is poorly controlled. Humans are particularly susceptible to sepsis. Sepsis is the leading cause of childhood death worldwide and contributes to a high proportion of hospitalized patient deaths.8 Hundreds of clinical studies that mostly inhibit proinflammatory cytokines have failed to improve treatment of sepsis, suggesting that cytokines are not the major mediators of septic death. These failures highlight our poor understanding of pyroptosis.

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