Fig. 3

Mechanism of action of the NLRP3 inflammasome. In the canonical pathway, the priming step involves the recognition of pathogen-associated molecular pattern (PAMP) or a danger-associated molecular pattern (DAMP) by a pattern recognition receptor (PRR) or toll-like receptor (TLR), which recruits the adaptor protein myeloid differentiation primary response 88 (MYD88) into the receptor complex leading to phosphorylation of the inhibitor of nuclear factor-kB (NFκB) IκB through interaction with the p50 and p65 transcription factors. Activation of the NF-κB pathway causes the synthesis of pro-IL-1-β or pro-IL-18. NLRP3 is activated by lysosomal-mediated cathepsin B via lysosome rupture, reactive oxygen species (ROS), oxidized mitochondrial (Mt) DNA, altered Ca2⁺ concentration via mitochondrial dysfunction, and adenosine triphosphate (ATP) efflux and potassium (K⁺) via pannexin1 (Panx1) channels. High extracellular ATP acts as a DAMP and binds to the purinergic receptor, P2X7 causing additional K⁺ efflux. Activation of NLRP3 involves oligomerization that results in activation of caspase-1 that converts pro-IL1β and pro-IL-18 into their mature forms. In addition, active caspase-1 cleaves Gasdermin D (GSDMD) into an N-terminus domain (GSDMD-N) and the autoinhibitory C-terminus domain (GSDMD-C). GSDMD-N binds to acidic phospholipids in the inner leaflet of the plasma membrane and oligomerizes to form pores that disrupt plasma membrane integrity, enabling release of IL-1β and IL-18 and inducing pyroptosis. The non-canonical pathway is activated by gram-negative bacteria or lipopolysaccharide (LPS) to activate caspase 4/5 in humans or caspase-11 in rodents that cleave GSDMD. The transient receptor protein channel 1 (TRPC1), a non-selective ion channel is also a substrate for caspase-11