Figure 2.

Activation mechanism of canonical and Noncanonical pyroptotic pathway. (A) Canonical inflammasome activation occurs in response to pathogen-associated molecular patterns (PAMPs) and host-derived danger-associated molecular pattern molecules (DAMPs). Responding to a variety of physiological or pathological changes, Inflammasome sensors, such as NLRP3, AIM2 and Pyrin, which contain a PYD may recruit adaptor protein apoptosis-associated speck-like protein (ASC) containing a caspase activation and recruitment domain (CARD) to mediate CARD–CARD interactions with effector protein pro-caspase-1. However, murine NLRP1b and NLRC4 contain a CARD and can interact directly with pro-caspase-1 without the ASC. After the above signal cascade response, inflammasomes activate pro-caspase-1 into active form. Activated caspase-1 cleaves pro-interleukin(IL)-1β and pro-IL-18 into their active forms. Caspase-1 also cleaves gasdermin D (GSDMD) to release the N-terminal domain (GSDMD-NT) which oligomerize on the cell membrane, forming membrane pores that induce the leakage of intracellular content inculding IL-1, IL-18, ATP and high mobility group protein box 1 (HMGB1) release and pyroptotic cell death. (B) Noncanonical pyroptotic pathway is mediated by human caspase-4/5 or murine caspase-11, which are activated by lipopolysaccharide (LPS) released from Gram-negative bacteria. Activated caspases cleave GSDMD into GSDMD-NT, leading to the formation of GSDMD pores. In addition, potassium(K+) efflux through those pores is enough to activate NLRP3 inflammasome, subsequently triggering caspase-1-dependent release of IL-1β and IL-18.