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1) Monosodium urate (MSU) crystal phagocytosis stimulates the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to generate reactive oxygen species that in turn can activate the NLRP3 (NOD-like receptor protein 3) inflammasome. (
2) MSU crystals may also stimulate the secretion of ATP, which can engage and activate the purinergic receptor P2X7, resulting in recruitment of pannexin-1 channels. The resultant rapid efflux of potassium, and the lowering of intracellular potassium, can also trigger inflammasome activation. (
3) Concurrently, MSU crystal interactions with Toll-like receptors (TLRs) on the cell surface stimulate the production of pro-IL-1β via MyD88- and NF-κB-dependent pro-IL-1β gene transcription. (
4) Once stimulated, the NLRP3 inflammasome’s enzymatic effector caspase-1 cleaves the pro-IL-1β to biologically active IL-1β. IL-1β is then secreted from the cell into the extra-cellular fluid of the site of inflammation. ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; IL-1β, interleukin-1 beta; NF-κB, nuclear factor-kappa B; NLRP3, NOD-like receptor protein 3; ROS, reactive oxygen species; TLR, Toll-like receptor.