| First Author | Ives A | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 6555 | PubMed ID | 25800347 |
| Mgi Jnum | J:221869 | Mgi Id | MGI:5641781 |
| Doi | 10.1038/ncomms7555 | Citation | Ives A, et al. (2015) Xanthine oxidoreductase regulates macrophage IL1beta secretion upon NLRP3 inflammasome activation. Nat Commun 6:6555 |
| abstractText | 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 IL1beta 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 IL1beta release and that XO blockade results in impaired IL1beta 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. |
