title: Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation.
abstract: Activation of the NLRP3 inflammasome by microbial ligands or tissue damage requires intracellular generation of reactive oxygen species (ROS). We present evidence that macrophage secretion of IL1β upon stimulation with ATP, crystals or LPS is mediated by a rapid increase in the activity of xanthine oxidase (XO), the oxidized form of xanthine dehydrogenase, resulting in the formation of uric acid as well as ROS. We show that XO-derived ROS, but not uric acid, is the trigger for IL1β release and that XO blockade results in impaired IL1β and caspase1 secretion. XO is localized to both cytoplasmic and mitochondrial compartments and acts upstream to the PI3K-AKT signalling pathway that results in mitochondrial ROS generation. This pathway represents a mechanism for regulating NLRP3 inflammasome activation that may have therapeutic implications in inflammatory diseases.
authors: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois, Ave Pierre Decker 4, 1011 Lausanne, Switzerland.
authors: Annette
authors: A
authors: Ives
authors: 1] Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois, Ave Pierre Decker 4, 1011 Lausanne, Switzerland [2] Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited, Hino, 1918512 Tokyo, Japan.
authors: Johji
authors: J
authors: Nomura
authors: Department of Biochemistry, University of Lausanne, chemin des Boveresses 155, 1066 Epalinges, Switzerland.
authors: Fabio
authors: 000000026969822X
authors: F
authors: Martinon
authors: Infectious Diseases laboratory, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors: Thierry
authors: 0000000293580109
authors: T
authors: Roger
authors: Infectious Diseases laboratory, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors: Didier
authors: D
authors: LeRoy
authors: Ardea Biosciences, San Diego, 92121 California, USA.
authors: Jeffrey N
authors: JN
authors: Miner
authors: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois, Ave Pierre Decker 4, 1011 Lausanne, Switzerland.
authors: Gregoire
authors: G
authors: Simon
authors: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois, Ave Pierre Decker 4, 1011 Lausanne, Switzerland.
authors: Nathalie
authors: N
authors: Busso
authors: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois, Ave Pierre Decker 4, 1011 Lausanne, Switzerland.
authors: Alexander
authors: A
authors: So
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002130:Calcium Phosphates / Q000494:pharmacology; D002352:Carrier Proteins / Q000187:drug effects / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000276:immunology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014527:Uric Acid / Q000276:immunology; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D014969:Xanthine Oxidase / Q000276:immunology*
chemical_list: D002130:Calcium Phosphates; D002352:Carrier Proteins; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D014527:Uric Acid; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D051057:Proto-Oncogene Proteins c-akt; D020170:Caspase 1; D002118:Calcium