Orchestration of NLRP3 Inflammasome Activation by Ion Fluxes

The assembly of the NLRP3 inflammasome can promote the release of IL-1β/IL-18 and initiate pyroptosis. Accordingly, the dysregulation of NLRP3 inflammasome activation is involved in a variety of human diseases, including gout, diabetes, and Alzheimer’s disease. NLRP3 can sense a variety of structurally unrelated pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to trigger inflammation, but the unifying mechanism of NLRP3 activation is still poorly understood. Increasing evidence suggests that intracellular ions, such as K+, Ca2+, and Cl−, have a significant role in NLRP3 inflammasome activation. Here, we review the current knowledge about the role of ionic fluxes in NLRP3 inflammasome activation and discuss how disturbances in intracellular ionic levels orchestrate different signaling events upstream of NLRP3. Ion fluxes, including K+ efflux, Ca2+ mobilization, and Cl− efflux, have been proposed as crucial events in NLRP3 inflammasome activation. K+ efflux is a distal upstream event and is sufficient to activate the NLRP3 inflammasome. The signaling pathways upstream of NLRP3 converge on Ca2+ release from the endoplasmic reticulum, which promotes mitochondrial damage and subsequent NLRP3 inflammasome activation. Cl− efflux acts downstream of mitochondrial damage and is a proximal upstream event for NLRP3 inflammasome activation. Intracellular ions can function as signaling messengers, effectively linking distinct events upstream of NLRP3 activation.