The mechanism regulating NLRP3 inflammasome activation in canonical, non-canonical, and alternate pathway

Schematic illustration of the mechanism regulating NLRP3 inflammasome activation in canonical, non-canonical, and alternate pathway. Optimal activation of NLRP3 requires two steps. The first step is priming, which is initiated by extracellular PAMPs and endogenous cytokines by the PRRs, which then upregulates the NF-κB-mediated transcription of NLRP3, pro-IL-1β, and pro-IL-18. The second step is activation, which includes canonical and non-canonical pathways. The canonical pathway is triggered by multiple pathogens and inflammatory agents through a combination of important and related events such as activation of the purinergic receptor P2X7 by ATP, cathepsin release following lysozyme rupture, opening of Ca2+ channels to allow ion flux, mitochondrial dysfunction, ROS formation, Golgi apparatus disassembly, and endoplasmic reticulum stress. Once activated, oligomerization of the NLRP3 inflammasome is thought to induce conformational changes that generate active caspase-1, which converts pro-pro-IL-1β and pro-IL-18 to mature bioactive IL-1β and IL-18. Additionally, Casp1 cleaves the protein gasdermin D to generate N-terminal gasdermin D to form pores, allowing IL-1β and IL-18 to leave the cell and effectively execute a highly inflammatory form of cell death that is termed pyroptosis. In the non-canonical pathway, intracellular LPS is directly recognized by the CARD domain of caspase-11 in mice and caspase-4/5 in humans, ultimately leading to IL-1β and IL-18 release through the activation of the NLRP3-ASC-Casp1 pathway. The alternative pathway of activation is caused by TLR4 agonists like LPS, which activates the TLR4-TRIF-RIPK1-FADD-Casp8 signaling pathway. Casp8 activates the NLRP3 inflammasome but lacks ASC speck formation, pyroptosis induction, or K+ efflux

Publication

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development (2024) Inamul Haque, et al. Int J Mol Sci. 2024 Jun;25(11). Figure: F1. Homo sapiens

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