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The crystalline particulate alum has widely been used as an adjuvant in vaccines. Alum and other crystalline particulates also stimulate NLRP3 (Nod‐like receptor protein 3)/caspase‐1 inflammasome assembly and secretion of mature IL‐1β via poorly understood mechanisms that involve destabilization of lysosomes and decreases in cytosolic K + . This study directly measures changes in cytosolic K + and characterizes mechanisms for K + efflux in LPS‐primed murine bone marrow‐derived macrophages (BMDM) stimulated with either Imject Alum or the lysosomal destabilizing agent leu‐leu‐OMe. IL‐1β secretion in response to either alum or leu‐leu‐OMe was inhibited by increased extracellular K + or decreased extracellular Na + . Atomic absorbance spectroscopy was used to directly demonstrate reduced intracellular K + upon stimulation with alum. Alum‐stimulated K + efflux and IL‐1β secretion was insensitive to several Trp channel antagonists. In contrast, pannexin1−/− BMDM demonstrated reduced IL‐1β release upon stimulation with alum. These observations indicate that combined efflux of intracellular K + and influx of extracellular Na + are necessary for optimal NLRP3 inflammasome activation in response to alum and lysosomal destabilization. Pannexin1 hemichannels may mediate in part the alum‐induced cation fluxes linked to NLRP3 inflammasome activation. (Supported by T32‐HL‐105338 and R01‐GM36387)
Katsnelson et al. (2013) studied this question.