Abstract
Inflammasomes are Nod-like receptor(NLR)- and caspase-1-containing cytoplasmic multiprotein complexes, which upon their assembly, process and activate the proinflammatory cytokines interleukin (IL)-1β and IL-18. The inflammasomes harboring the NLR members NALP1, NALP3 and IPAF have been best characterized. While the IPAF inflammasome is activated by bacterial flagellin, activation of the NALP3 inflammasome is triggered not only by several microbial components, but also by a plethora of danger-associated host molecules such as uric acid. How NALP3 senses these chemically unrelated activators is not known. Here, we provide evidence that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K+ efflux from cells. Low intracellular K+ is also a requirement for NALP1 inflammasome activation by lethal toxin of Bacillus anthracis. In vitro, NALP inflammasome assembly and caspase-1 recruitment occurs spontaneously at K+ concentrations below 90 mM, but is prevented at higher concentrations. Thus, low intracellular K+ may be the least common trigger of NALP-inflammasome activation.
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Abbreviations
- Il-1β:
-
interleukin-1β
- PAMPs:
-
pathogen-associated molecular patterns
- NLRs:
-
NOD-like receptors
- MDP:
-
muramyl-di-peptide
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Acknowledgements
We thank C Mattmann, Rosa Castillo and Aubry Tardivel for technical support, and Helen Everet and Dan Muruve for the critical reading of the manuscript. We thank Sanjeev Mariathasan and Vishva M Dixit for the generous gift of the ASC and IPAF knock-out mice. This work was supported by grants of the Swiss National Science Foundation and the Commission of Technology and Innovation (CTI). VP and SP are supported by a Marie Curie Intra European Fellowship. CD is supported by the Fondation pour la Recherche Médicale. FM is recipient of a Human Frontier Science fellowship.
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Pétrilli, V., Papin, S., Dostert, C. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14, 1583–1589 (2007). https://doi.org/10.1038/sj.cdd.4402195
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DOI: https://doi.org/10.1038/sj.cdd.4402195
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