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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy
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Blotting, Western
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Calcium / metabolism
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Calcium Phosphates / pharmacology
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Carrier Proteins / drug effects
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Carrier Proteins / immunology*
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Caspase 1 / immunology
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Gene Knockdown Techniques
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In Vitro Techniques
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Interleukin-1beta / metabolism*
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Lipopolysaccharides / pharmacology
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Macrophages / immunology
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Macrophages / metabolism*
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Mice
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Mice, Inbred C57BL
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Monocytes
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NLR Family, Pyrin Domain-Containing 3 Protein
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Peritonitis / immunology
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / immunology*
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Uric Acid / immunology
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Xanthine Dehydrogenase / antagonists & inhibitors
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Xanthine Dehydrogenase / genetics*
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Xanthine Dehydrogenase / immunology
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Xanthine Oxidase / immunology*
Substances
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Calcium Phosphates
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Carrier Proteins
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Interleukin-1beta
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, mouse
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Reactive Oxygen Species
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Uric Acid
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Xanthine Dehydrogenase
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Xanthine Oxidase
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Proto-Oncogene Proteins c-akt
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Caspase 1
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Calcium