Fig. 2

The pyroptosis pathways. In the canonical pathway, exogenous pathogens and endogenous damage are recognized by the intracellular sensor proteins, such as NLRP1, NLRC4, NLRP3, AIM2, and Pyrin, and then activate caspase-1. In the non-canonical pathway, intracellular LPS binds directly to caspase-4/5 in humans and caspase-11 in mice and results in activation of these caspases. Activated caspase-1/4/5/11 cleave GSDMD; the N-terminal domain is liberated, which forms pores on cell membrane and results in cytoplasmic swelling, membrane rupture, and the release of cytosolic contents. Activated caspases also cleave pro-inflammatory cytokines IL-1β and IL-18, leading to maturation of IL-1β and IL-18 that are released from the pores on the cell membrane and amplify the local or systemic inflammation