Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 inflammasome: From action mechanism to therapeutic target in clinical trials

Figure 1 Molecular signaling of nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 priming and activation. Pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors [such as toll-like receptors (TLRs)) can activate the nuclear factor kappa B (NF-kappaB) signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway, which both initiate the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) priming process, including the upregulation of NLRP3 and pro-interleukin (IL)-1β protein expression. Meanwhile, the assembled NLRP3 inflammasome also cleaves the gasdermin D (GSDMD) by disconnecting the C-terminal to produce GSDMD-N, leading to cell pyroptosis. Additionally, endoplasmic reticulum (ER) stress-induced Ca²⁺ efflux, the imbalance of Ca²⁺ and K⁺-associated mitochondrial reactive oxygen species (ROS) stress, and lysosome damage-produced cathepsin B can serve as triggers for NLRP3 activation to accelerate the assembly of the NLRP3 inflammasome. The cartoons in this figure were prepared using Biorender (https://biorender.com). ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain; NEK7: Never in mitosis A-related kinase 7; NEMO: Nuclear factor kappa B essential modulator; PRRS: Pattern recognition receptors.