title: Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation.
abstract: Activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome initiates an inflammatory response, which is associated with host defense against pathogens and the progression of chronic inflammatory diseases such as gout and atherosclerosis. The NLRP3 inflammasome mediates caspase-1 activation and subsequent IL-1β processing in response to various stimuli, including extracellular ATP, although the roles of intracellular ATP (iATP) in NLRP3 activation remain unclear. In this study, we found that in activated macrophages artificial reduction of iATP by 2-deoxyglucose, a glycolysis inhibitor, caused mitochondrial membrane depolarization, leading to IL-1β secretion via NLRP3 and caspase-1 activation. Additionally, the NLRP3 activators nigericin and monosodium urate crystals lowered iATP through K(+)- and Ca(2+)-mediated mitochondrial dysfunction, suggesting a feedback loop between iATP loss and lowering of mitochondrial membrane potential. These results demonstrate the fundamental roles of iATP in the maintenance of mitochondrial function and regulation of IL-1β secretion, and they suggest that maintenance of the intracellular ATP pools could be a strategy for countering NLRP3-mediated inflammation.
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan; and Service de Rhumatologie, Département de l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, Université de Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Johji
authors.initials: J
authors.lastname: Nomura
authors.affiliation: Service de Rhumatologie, Département de l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, Université de Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.affiliation: Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Ltd., Hino, Tokyo 191-8512, Japan; and.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Service de Rhumatologie, Département de l'Appareil Locomoteur, Centre Hospitalier Universitaire Vaudois, Université de Lausanne, 1011 Lausanne, Switzerland Nathalie.Busso@chuv.ch.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D042541:Intracellular Space; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009550:Nigericin / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; C102717:Lrrn3 protein, mouse; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D014527:Uric Acid; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D020170:Caspase 1; D009550:Nigericin