Fig. 4: Regulation mechanism of pyroptosis.
From: Regulation of apoptosis, ferroptosis, and pyroptosis mediated by acetylation
Pyroptosis primarily consists of three stages. First, DAMPs (ATP, heat shock proteins, high mobility group box 1 (HMGB1)), PAMPs (LPS, peptidoglycan, viral double-stranded RNA), cytokines, neurohormones, etc., enter the cell through receptors such as TLR/IL-1R, cytokine receptors, and GPCRs, activating NF-κB, which in turn promotes the transcription of mRNA for NLRP3, ASC, pro-caspase-1, pro-IL-1β, pro-IL-18, GSDMD, among others. Following the translation, the NLRP3 protein forms a complex with NEK7, which, under the influence of BTK, further interacts with ASC to create the second phase of the complex. This complex continues to associate with Pro-caspase-1, culminating in the formation of the inflammasome. The inflammasome senses various pathogens, cellular damage signals, or metabolic abnormalities, triggering the activation of downstream caspase-1. Caspase-1 cleaves and converts pro-IL-1β and pro-IL-18 into their active forms, while also cleaving GSDMD to generate GSDMD-NT. During this phase, both autophagy and mitophagy inhibit the generation of NLRP3. However, elevated levels of ROS and the unfolded protein response lead to the release of TXNIP from thioredoxin, promoting the activation of NLRP3 and the subsequent formation of the inflammasome. Additionally, Cathepsin B within the lysosome also facilitates the generation of NLRP3. In the final stage, GSDMD-NT forms 21-nanometer pores, driving the extracellular release of IL-1β and IL-18, as well as the loss of membrane integrity, ultimately leading to cell death and the release of inflammatory mediators. DAMPs damage-associated molecular patterns, PAMPs pathogen-associated molecular patterns, LPS lipopolysaccharide, TLR/IL-1R toll-like receptor/Interleukin-1 receptor, GPCR G protein-coupled receptor, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, NLRP3 NOD-like receptor family, pyrin domain-containing 3, ASC apoptosis-associated speck-like protein containing a CARD, Pro-IL-1β pro-interleukin-1 beta, Pro-IL-18 pro-interleukin-18, GSDMD gasdermin D, NEK7 NIMA-related kinase 7, BTK Bruton tyrosine kinase, IL-1β interleukin-1 beta, IL-18 interleukin-18, GSDMD-NT N-terminal fragment of gasdermin D, TXNIP thioredoxin-interacting protein.
