Figure 2.

Activation of the NLRP3 inflammasome and canonical pyroptosis in liver cells. Various stimuli of liver damage might cause hepatocyte cell death and gut dysbiosis, leading to high exposure to DAMPs and PAMPs that activate liver inflammasomes: (A) In hepatocytes, NLRP3 inflammasome activation requires two steps: the priming signal (SIGNAL 1) is initiated by PAMPs such as LPS, which bind to their corresponding TLR and upregulate the expression of pro-IL-1β, pro-IL-18, pro-caspase-1, and NLRP3 genes via NF-ƙB signaling activation. The second signal (SIGNAL 2) is triggered by PAMPs and/or DAMPs and activates NLRP3, which, in turn, activates pro-caspase-1. Activated casp-1 cleaves IL-1β and IL-18 precursors into mature and proinflammatory forms that are secreted to extracellular space. Casp-1 and, alternatively, caspase-4/5/11 might also cleave protein GSDMD. The N-terminal fragment of GSDMD (N-GSDMD) forms pores in the plasma membrane, inducing pyroptosis by cell swelling and osmotic lysis. (B) Inflammasome activation and pyroptosis also occurs in nonparenchymal cells. DAMPSs and gut-derived PAMPs activate Kupffer cells via PRRs, triggering the production of IL-1β and, subsequently, CCL2 and TNF. NLRP3 activation in HSC also induces the expression of the profibrogenic molecule TGF-β. Together, these events result in liver inflammation and fibrosis, perpetuating liver damage and hepatocellular carcinoma. Abbreviations: CCL2, C-C motif chemokine ligand 2; DAMPS, damage-associated molecular patterns; GSDMD, gasdermin D; HSCs, hepatic stellate cells; KCs, Kupffer cells; LPS, liposaccharide; NF-ƙc, nuclear factor kappa-light-chain-enhancer of activated B cells NLRP3, NLR family pyrin domain containing 3; PAMPs, pathogen-associated molecular patterns; PRRs, pattern recognition receptors; TLR, toll-like receptor; TNF, tumor-nuclear factor; TGF-β, transforming growth factor beta. Created with BioRender.com.