title: Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation.
abstract: Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Shankar S
authors: SS
authors: Iyer
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Qiong
authors: Q
authors: He
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: John R
authors: JR
authors: Janczy
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Molecular and Cellular Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Eric I
authors: EI
authors: Elliott
authors: Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Zhenyu
authors: Z
authors: Zhong
authors: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Alicia K
authors: AK
authors: Olivier
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Jeffrey J
authors: JJ
authors: Sadler
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Vickie
authors: V
authors: Knepper-Adrian
authors: the Department of Cell & Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Renzhi
authors: R
authors: Han
authors: Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
authors: Liang
authors: L
authors: Qiao
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Stephanie C
authors: SC
authors: Eisenbarth
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Veterans Affairs Medical Center, Iowa City, IA 52241, USA.
authors: William M
authors: WM
authors: Nauseef
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors: Suzanne L
authors: SL
authors: Cassel
authors: Inflammation Program, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Graduate Program in Molecular and Cellular Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.|Veterans Affairs Medical Center, Iowa City, IA 52241, USA.
authors: Fayyaz S
authors: FS
authors: Sutterwala
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002308:Cardiolipins / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000069349:Linezolid; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D023303:Oxazolidinones / Q000378:metabolism / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000081:Acetamides; D002308:Cardiolipins; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D023303:Oxazolidinones; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; D000069349:Linezolid; D011188:Potassium
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