K+ regulates Ca2+ to drive inflammasome signaling: dynamic visualization of ion flux in live cells
Open accessAbstract
P2X7 purinergic receptor engagement with extracellular ATP induces transmembrane potassium and calcium flux resulting in assembly of the NLRP3 inflammasome in LPS-primed macrophages. The role of potassium and calcium in inflammasome regulation is not well understood, largely due to limitations in existing methods for interrogating potassium in real time. The use of KS6, a novel sensor for selective and sensitive dynamic visualization of intracellular potassium flux in live cells, multiplexed with the intracellular calcium sensor Fluo-4, revealed a coordinated relationship between potassium and calcium. Interestingly, the mitochondrial potassium pool was mobilized in a P2X7 signaling, and ATP dose-dependent manner, suggesting a role for mitochondrial sensing of cytosolic ion perturbation. Through treatment with extracellular potassium we found that potassium efflux was necessary to permit sustained calcium entry, but not transient calcium flux from intracellular stores. Further, intracellular calcium chelation with BAPTA-AM indicated that P2X7-induced potassium depletion was independent of calcium mobilization. This evidence suggests that both potassium efflux and calcium influx are necessary for mitochondrial reactive oxygen generation upstream of NLRP3 inflammasome assembly and pyroptotic cell death. We propose a model wherein potassium efflux is necessary for calcium influx, resulting in mitochondrial reactive oxygen generation to trigger the NLRP3 inflammasome.
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This binding elicits activation of the NLRP3 inflammasome in LPS-stimulated macrophages, causing secretion of IL-18 and IL-1β, and may promote maintenance and function of the epithelial barrier.
“this has been shown to elicit activation of the NLRP3 inflammasome in LPS-stimulated macrophages, which causes secretion of IL-18 (but also of the pro-inflammatory cytokine IL-1β) and may thus promote maintenance and function of the epithelial barrier (Mariathasan et al., 2006; Sutterwala et al., 2014; 2006; Yaron et al., 2015).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Yaron et al., 2015
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BackgroundIon homeostasis, channels, and transporters: an update on cellular mechanisms
Dubyak, G. (2004) · AJP Advances in Physiology Education · doi:10.1152/advan.00046.2004 · Cited by 153 · cited 3× · see citing works
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“P2X7 has multiple ATP-sensing sites that have been shown to dose dependently affect the level of pore dilation permissive to ion flux.(36) It is still not well understood how mitochondria respond to cytosolic potassium, but we speculate that this may occur either through mitochondrial potassium channels or transient l…”
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“This mechanism of inhibition would be contrary to the previously described promotion, not inhibition, of inflammasome assembly due to zinc ion chelation.(41) This study establishes a previously unknown relationship between potassium and calcium during purinergic receptordependent activation of the NLRP3 inflammasome.”
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“To date, Arlehamn et al.31 have reported the only live-cell imaging experiments on potassium in macrophages stimulated to undergo inflammasome assembly by infection with Pseudomonas.”
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“Potassium efflux and ROS generation have independently been proposed as downstream effects of P2X7 activation.(33) By live-cell imaging, we identified a rapid and robust mitochondrial potassium mobilization associated with P2X7 engagement.”
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“It was recently reported that membrane permeability is dose dependently related to P2X7 receptor activation, but it is unknown whether potassium efflux is similarly dose dependent.(24) We observed a dose dependence of both potassium efflux and membrane permeability as indicated by the response in the KS6 potassium sen…”
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“This provides additional support for the observation that mitochondria respond to cytosolic potassium levels, as it was previously shown that mitochondria are capable of sequestering and buffering cytosolic potassium.(35) A mitochondrial potassium buffering mechanism is further supported by our finding that efflux is…”
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BackgroundIntegrating epigenetic data into molecular casual networks
Yoo, S., Lee, E., & Zhu, J. (2014) · Molecular Pain · doi:10.1186/1744-8069-10-s1-o21 · Cited by 5 · see citing works
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- Murakami T, Ockinger J, Yu J, Byles V. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci USA 2012; 109: 11282–11287. 22733741 PMC3396518
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“Because almost all NLRP3-activating stimuli converge to K efflux (Muñoz-Planillo et al., 2013; Yaron et al., 2015), it is reasonable”
BackgroundHow location and cellular signaling combine to activate the NLRP3 inflammasome
Akbal, A., Dernst, A., Lovotti, M., Mangan, M., McManus, R. M., & Latz, E. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00922-w · Cited by 250 · see citing works
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“Furthermore, a recent study showed that K efflux mediates the influx of Ca, which causes mitochondrial Ca overload, resulting in mitochondrial dysfunction (Yaron et al. 2015).”
BackgroundUpdated insights into the molecular networks for NLRP3 inflammasome activation
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“Finally, one study proposed that Ca 2+ influx into the cytosol follows K + efflux caused by NLRP3 stimuli and that this Ca 2+ flux promotes activation of the inflammasome by enhancing mitochondrial ROS generation 52 .”
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“Subsequently, K efflux promotes the release of ER-linked Ca2+ stores [36].”
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“Subsequently, the release of ER-linked Ca is promoted by K efflux (32, 52).”
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“The most prevailing inflammasome activating mechanism involves changes in cytosolic K+ concentration (Pétrilli et al., 2007; Yaron et al., 2015).”
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“The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome, the best characterized member of Nod-like receptor family, is a multiprotein complex that contains the NLRP3, adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the precursor caspase-1 (Davis et al., 2011; Schroder and Tsc…”
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“K efflux triggers Cl channel-mediated dye uptake In mouse macrophages, P2X7Rs are thought to trigger dye uptake by depleting intracellular K [66].”
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“A recent study demonstrated in macrophages that K efflux and Ca2+ influx through P2x7 were required for sustained reduction of the mitochondrial membrane potential and generation of mitochondrial ROS formation upstream of NLRP3 inflammasome assembly and pyroptotic cell death (35).”
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“In addition, Na influx accompanied by water influx diminishes the cytosolic K concentration below the threshold, leading to inflammasome activation.(79) Notably, reactive oxygen species (ROS) induce inflammasome aggregation and IL‐1β release, secondary to P2X7R activation.”
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“Radiation treatment increases ROS production and releases mitochondrial DNA into cytosol (37, 38) and induces Ca2+ and K+ influx, which can activate the NLRP3 inflammasome (39).”
BackgroundEffects of Microglial Activation and Polarization on Brain Injury After Stroke
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Advances in the molecular mechanisms of NLRP3 inflammasome activators and inactivators
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“This process is related to several other immunological functions, especially in inflammasome activation [58,59].”
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Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway
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“K efflux also controls Ca release from the ER demonstrating the interconnection between the different activating signals (43, 44).”
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“…cells can also signal locally through paracrine receptors (e.g. P2X7) to promote K+ release leading to uptake of extracellular Ca2+, which is associated with an increase in the expression and release of cytokines including IL-1β (Jantaratnotai et al., 2009; Wilson et al., 2007; Yaron et al., 2015).”
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“Extracellular ATP, a well-known NLRP3 activator, binds to the P2X7 receptor, inducing K+ efflux, which could cause mitochondrial disruption [127].”
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“This depolarizes the mitochondrial membrane, generating ROS and oxidized mitochondrial DNA (ox-mtDNA), which reactivates NLRP3 [46, 47].”
BackgroundInfluentialInflammasomes: Mechanisms of Action and Involvement in Human Diseases
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Cellular Models and Assays to Study NLRP3 Inflammasome Biology
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“1 cells have been used by Yaron and collaborators to demonstrate that K+ efflux is upstream of Ca2+ influx in the production of mtROS, thus beginning the cascade of events leading to NLRP3 inflammasome activation [75].”
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A mini-review on ion fluxes that regulate NLRP3 inflammasome activation
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The NLRP3 inflammasome: role in the pathobiology of chronic pain
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The Mechanism and Regulation of the NLRP3 Inflammasome during Fibrosis
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Promise of the NLRP3 Inflammasome Inhibitors in In Vivo Disease Models
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“An increment in cellular Ca2+ can evoke NLRP3 activation by processes that are still nebulous; on the other hand, calcium channel inhibition precludes NLRP3 stimulation [262,263].”
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“Furthermore, the binding of P2X7 purinergic receptor with extracellular ATP results in an efflux of intracellular K+ that induces assembly and activation of NLRP3 inflammasome in LPS-primed macrophages (Yaron et al., 2015).”
BackgroundActivation and Pharmacological Regulation of Inflammasomes
Chen, C., & Xu, P. (2022) · Biomolecules · doi:10.3390/biom12071005 · Cited by 59 · see citing works
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“K efflux promotes ER Ca efflux followed by plasma Ca channels activation (Yaron et al., 2015).”
BackgroundDifferential Ca2+ mobilization and mast cell degranulation by FcεRI- and GPCR-mediated signaling
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“This increased permeability is linked to facilitation of P2X7R currents (33) and several other physiological functions such as inflammasome activation (34, 35), inhibition of phagocytosis (36), activation of p38 MAPK (37, 38), and the production of nitrites and reactive oxygen species (ROS) (39).”
BackgroundMicrobe-metabolite-host axis, two-way action in the pathogenesis and treatment of human autoimmunity
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NLRP3 inflammasome activation, metabolic danger signals, and protein binding partners
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“Indeed, the efflux of cellular ions such as the potassium ions through the toxins pores, and the subsequent decrease of cellular potassium concentration, activate the NLRP3 inflammasome (Yaron et al., 2015), leading to pyroptosis (Fink and Cookson, 2006).”
BackgroundP2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis
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“This is supported by experiments showing that not only ATP, but also other agents that induce K+ efflux, such as the ionophore nigericin or crystalline molecules, elicit inflammasome activation too (Compan et al., 2012; Yaron et al., 2015).”
BackgroundAssessing NLRP3 Inflammasome Activation by Nanoparticles
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The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome
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NLPR3 Inflammasomes and Their Significance for Atherosclerosis
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“Then, it induces the overburden of mitochondrial Ca2+ and culminates in mitochondrial dysfunction [36].”
BackgroundThe Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury
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“As such, Ca2+ influx and K+ efflux are often found to be coordinated in NLRP3 activation (Yaron et al., 2015).”
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Core Hydrophobicity of Supramolecular Nanoparticles Induces NLRP3 Inflammasome Activation
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“In contrast, nigericin is a K+ ionophore, which promotes the influx of Ca2+ by inducing the efflux of mitochondrial K+ [57].”
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NLRP3 Inflammasome Activation in Liver Disorders: From Molecular Pathways to Therapeutic Strategies
Ma, W., Wang, Y., & Liu, J. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s532908 · Cited by 32 · see citing works
“28 Subsequent caspase-1 activation promotes pyroptosis and IL-1β/IL-18 release, perpetuating chronic inflammation and fibrosis through hepatic stellate cells (HSCs) activation.”
- Authors
- Yaron, J. R., Gangaraju, S., Rao, M. Y., Kong, X., Zhang, L., Su, F., Tian, Y., Glenn, H. L., & Meldrum, D. R.
- Affiliations
- Arizona State University (US)
- Corresponding author
- Meldrum, D R
- Venue
- Cell Death & Disease
- Published
- 2015-10-29
- Volume
- 6
- Issue
- 10
- Pages
- e1954-e1954
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC5399176
- OpenAlex
- W2212334792
- Cited by
- 212
- References
- 44
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 20 · 2023: 25 · 2022: 21 · 2021: 22 · 2020: 25 · 2019: 18 · 2018: 23 · 2017: 14 · 2016: 11
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (P50HG002360)
- National Cancer Institute (U01CA164250)
- Common Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- P2X7 receptor, NLRP3 inflammasome, potassium efflux, calcium influx, Fluo-4, mitochondrial reactive oxygen species, pyroptosis, macrophages, LPS priming, extracellular ATP, BAPTA-AM
- MeSH terms
- Adenosine Triphosphate, Animals, Calcium, Cell Line, Macrophages, Mitochondria, Models, Biological, Potassium, Reactive Oxygen Species, Calcium Signaling, Mice, Receptors, Purinergic P2X7, Inflammasomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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