Editors' ChoiceImmunology

Potassium Controls the Inflammasome

Sci. Signal.  09 Jul 2013:
Vol. 6, Issue 283, pp. ec156
DOI: 10.1126/scisignal.2004489

The NLRP3 inflammasome is a multiprotein complex that is required for the processing and production of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Activation of the inflammasome occurs in two steps. First, signaling by Toll-like receptors (TLRs) or certain inflammatory cytokines stimulates the nuclear factor κB (NF-κB)–dependent expression of genes encoding NLRP3, pro–IL-1β, and pro–IL-18. A second signal stimulates assembly of the inflammasome, activation of caspase-1, and the processing of pro–IL-1β and pro–IL-18 into their active forms. Given that this second step is triggered by factors as diverse as ATP, particulate matter, and membrane pore–forming toxins, among others, it is thought unlikely that NLRP3 binds directly to these stimuli (see commentary by Kanneganti and Lamkanfi). Muñoz-Planillo et al. tested the effects of multiple NLRP3 activators on TLR-stimulated mouse bone marrow–derived macrophages and found that mitochondrial dysfunction, the production of reactive oxygen species, or an increase in cell swelling were not required for inflammasome activation. The only effect that was common to all stimuli was a reduction in the concentration of intracellular potassium ions (K+). Efflux of K+ was accompanied by the influx of sodium ions (Na+); however, whereas influx of Na+ modulated inflammasome activation, it was not essential. Incubation of TLR-stimulated wild-type, but not NLRP3-deficient, macrophages in K+-free medium was sufficient to stimulate IL-1β secretion in the absence of known NLRP3 activators. Together, these data suggest that efflux of intracellular K+ is the common link among the diverse stimuli that trigger activation of the NLRP3 inflammasome.

R. Muñoz-Planillo, P. Kuffa, G. Martínez-Colón, B. L. Smith, T. M. Rajendiran, G. Núñez, K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013). [PubMed]

T.-D. Kanneganti, M. Lamkanfi, K+ drops tilt the NLRP3 inflammasome. Immunity 38, 1085–1088 (2013). [PubMed]