Fig. 1

NLRP3 inflammasome activation involves two steps. In the priming step, activation of TLR4, TNFR or IL-1R1 leads to activation of NF-kB, which subsequently translocates to the nucleus and induces the transcription of pro-IL-1β, ASC (also known as PYCARD) and NLRP3. NLRP3 is autoinihibted in the cytosol and remains in the autoinhibited state after the priming step. An activating signal is necessary to release the autoinhibition. Activated NLRP3 can undergo oligomerization through homotypic NACHT domain interactions to form the inflammasome complex. NLRP3 oligomers induce the filament assembly of ASC (PYCARD) into ASC specks through homotypic PYD interactions. ASC specks act as a molecular platform to recruit pro-caspase-1 through homotypic CARD interactions. Pro-caspase-1 undergoes autoproteolysis to generate active caspase-1, which can cleave pro-forms of IL-1β and IL-18 into their mature forms. Caspase-1 can also cleave gasdermin D (GSDMD) into its N-terminal fragment (GSDMD-N), which translocates to the plasma membrane and forms a pore, through which IL-1β and IL-18 are released into the extracellular space (ECS). NLRP3, nucleotide-binding domain (NOD)-like receptor protein 3; ASC, apoptosis-associated speck-like protein; PYD, pyrin-like domain; CARD, caspase recruitment domain; LRR, leucine-rich repeat. Figure created in BioRender.com [55, 61, 62]