Fig. 2

Pyroptosis is an inflammatory form of cell death triggered by intracellular sensors such as NLRP3 (used here as an example) that detect DAMPs, PAMPs, membrane disturbances, osmotic imbalances, and ion efflux, among other stimuli. Upon activation, these sensors recruit the adapter ASC, forming a micron-sized structure called the inflammasome. These oligomeric structures act as platforms for the activation of caspase-1. Active caspase-1 cleaves proforms of the interleukin-1 family cytokines IL-1β and IL-18. Caspase-1 also activates gasdermin D (GSDMD), unmasking the N-terminal domain, which forms pores in the plasma membrane, in turn enabling the release of mature IL-1β and IL-18 and causing cell swelling (a “ballooning effect”) and pyroptosis. In addition, intracellular recognition of LPS can result in pyroptosis: guanylate-binding proteins (GBPs) bind to the surface of bacteria and assemble a caspase-4/11-activating platform composed of GBP1, 2, 3, and 4, and the cytosolic precursors of caspase-4 and -11. Active caspase-4 and -11 cleave GSDMD, leading to pyroptosis. Notably, caspase-4 can additionally induce proteolytic cleavage of IL-18. As an inherently inflammatory form of cell death, pyroptosis has several layers of regulation. Expression of NLRP3 and the cytokine IL-1 requires priming via stimulation of TLRs, TNFR or IL-1R followed by NFκB activation. Inflammasome sensors are heavily regulated through posttranslational modifications, such as phosphorylation and ubiquitylation (indicated in the box) or by cleavage