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Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation

Author

Listed:
  • Annette Ives

    (Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois)

  • Johji Nomura

    (Rheumatology Laboratory, Centre Hospitalier Universitaire Vaudois
    Pharmaceutical Development Research Laboratories, Teijin Institute for Bio-Medical Research, Teijin Pharma Limited)

  • 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)

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.

Suggested Citation

  • Annette Ives & Johji Nomura & Fabio Martinon & Thierry Roger & Didier LeRoy & Jeffrey N. Miner & Gregoire Simon & Nathalie Busso & Alexander So, 2015. "Xanthine oxidoreductase regulates macrophage IL1β secretion upon NLRP3 inflammasome activation," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7555
    DOI: 10.1038/ncomms7555
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