Mechanisms of human NLRP3 inflammasome activation and regulation

The mechanisms of human NLRP3 inflammasome activation and regulation. The activation of NLRP3 inflammasome occurs either through a canonical two-step pathway or a non-canonical pathway, and a direct or alternative pathway. The canonical activation pathway involved 2 steps: a priming (signal 1, left panel) and an activation (signal 2, second panel from left) steps. Priming step is induced by NLRP3 signals, including LPS and TNF, IL-1b, IFNs, lipopolysaccharide (LPS), and sphingosine-1 phosphate (S1P), activate NF-κB that; in turn upregulates the transcription of Nlrp3 gene and other genes (ASC and pro-caspase1) involved in NLRP inflammasome, by interacting with and triggering their receptors. Once transcribed, NLRP3 is pre-activated by interacting with NEK7, forming a complex that will be activated into hetero-complex inflammasome. The canonical activation of NLRP3 inflammasome is induced by signal 2 including PAMPs (nigericin, viral RNA, and MDP) and DAMPs (extracellular ATP, mtDNA, and mtROS) and particulates. The molecular mechanisms behind the polymerization and the activation of NLRP3 inflammasome include activation of several signaling events, including induction of K+ efflux, Ca2+ flux, Cl–efflux, lysosomal disruption, mtROS production, and release of oxidized mtDNA in the cytosolic compartment. Thus, formation of NLRP3 inflammasome includes oligomerization of NLRP3-NEK7, recruitment of ASC, and Casp1. auto-proteolysis of proteolytic cleavage of Casp1 releases p10/p20 active enzyme, which digest Pro-IL-1β and Pro-IL-18 into IL-1β and IL-18 cytokines to promote proinflammatory responses. The subunit p10/p20 of Casp1 also digests GSDMD releasing GSDMD-N that form cell membrane pore to result in pyroptosis of the cell. Non-canonical activation of NLRP3 inflammasome (third panel from left) occurs without priming, as Casp4 is already present in the cytoplasm, and is induced by gram-negative bacteria that release LPS into the cell cytosol. Released LPS activates Casp11 in human (and Casp4/5 in mouse), which cleaves GSDMD complex releasing GSDMD-N that forms gasdermin pores and induces pyroptosis. The gasdermin pore formed constitutes a channel for K+ efflux, which activates the NLRP3 inflammasome, and consequently activate Casp1 and IL-1β and IL-18. The alternative pathway (right panel) activation is induced by TLR4 agonists that activates the TLR4-TRIF-RIPK1-FADD-Casp8 signaling pathway. Consequently, Casp8 activates the NLRP3 inflammasome. Note that, there is no need of K+ efflux, ASC speck formation, to activate inflammasome, and there is no pyroptosis

Publication

NLRP inflammasomes in health and disease (2024) Zhihao Xu, et al. Mol Biomed. 2024 Dec;5(NA). Figure: F5. Homo sapiens

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