Xanthine oxidoreductase regulates macrophage IL1[beta] secretion upon NLRP3 inflammasome activation

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...

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Bibliographic Details
Published in:Nature communications 2015-03, Vol.6, p.6555
Main Authors: Ives, Annette, Nomura, Johji, Martinon, Fabio, Roger, Thierry, Leroy, Didier, Miner, Jeffrey N, Simon, Gregoire, Busso, Nathalie, So, Alexander
Format: Article
Language:English
Subjects:
Adenosine triphosphate
Crystals
Dehydrogenases
Enzymes
Laboratories
Peritonitis
Uric acid
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Summary: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.
ISSN:2041-1723
DOI:10.1038/ncomms7555