Abstract
The NLRP3 inflammasome is an important component of the innate immune system. However, its mechanism of activation remains largely unknown. We show that NLRP3 activators including bacterial pore-forming toxins, nigericin, ATP, and particulate matter caused mitochondrial perturbation or the opening of a large membrane pore, but this was not required for NLRP3 activation. Furthermore, reactive oxygen species generation or a change in cell volume was not necessary for NLRP3 activation. Instead, the only common activity induced by all NLRP3 agonists was the permeation of the cell membrane to K⁺ and Na⁺. Notably, reduction of the intracellular K⁺ concentration was sufficient to activate NLRP3, whereas an increase in intracellular Na⁺ modulated but was not strictly required for inflammasome activation. These results provide a unifying model for the activation of the NLRP3 inflammasome in which a drop in cytosolic K⁺ is the common step that is necessary and sufficient for caspase-1 activation.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / pharmacology
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Animals
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Carrier Proteins / drug effects
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Caspase 1 / metabolism
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Cell Membrane Permeability / drug effects
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Cells, Cultured
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Enzyme Activation / drug effects
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Immunity, Innate
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Inflammasomes / drug effects
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Inflammasomes / metabolism*
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Macrophages / drug effects
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Macrophages / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / drug effects
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Mitochondria / metabolism*
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nigericin / pharmacology
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Particulate Matter / pharmacology
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Potassium / metabolism
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Potassium Channels / drug effects
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Potassium Channels / metabolism
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Reactive Oxygen Species / metabolism
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Sodium Channels / drug effects
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Sodium Channels / metabolism
Substances
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Carrier Proteins
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Inflammasomes
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Particulate Matter
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Potassium Channels
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Reactive Oxygen Species
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Sodium Channels
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Adenosine Triphosphate
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Caspase 1
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Nigericin
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Potassium