Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation

Annette Ives, Johji Nomura, Fabio Martinon, Thierry Roger, Didier LeRoy, Jeffrey N. Miner, Gregoire Simon, Nathalie Busso and Alexander So ()
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Annette Ives: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois
Johji Nomura: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois
Fabio Martinon: University of Lausanne
Thierry Roger: Infectious Diseases laboratory, Centre Hospitalier Universitaire Vaudois
Didier LeRoy: Infectious Diseases laboratory, Centre Hospitalier Universitaire Vaudois
Jeffrey N. Miner: Ardea Biosciences
Gregoire Simon: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois
Nathalie Busso: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois
Alexander So: Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7555

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