Involvement of xanthine oxidase and hypoxia-inducible factor 1 in Toll-like receptor 7/8-mediated activation of caspase 1 and interleukin-1β.
Inflammatory reactions to ssRNA viruses are induced by the endosomal Toll-like receptors (TLRs) 7 and 8. TLR7/8-mediated inflammatory reaction results in activation of the Nalp3 inflammasome via an unknown mechanism. Here we report for the first time that TLR7/8 mediate activation of xanthine oxidase (XOD) in an HIF-1α-dependent manner. XOD produces uric acid and reactive oxygen species, which could activate Nalp3 and therefore induce activation of caspase 1, known to convert inactive pro-IL-1β into active IL-1β. Specific inhibition of the XOD activity attenuates TLR7/8-mediated activation of caspase 1 and IL-1β release. These results were obtained using human THP-1 myeloid macrophages. The findings were verified by conducting in vivo experiments on mice.
Nicholas
Sally A
SA
Medway School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
Bubnov
Vladimir V
VV
Yasinska
Inna M
IM
Sumbayev
Vadim V
VV
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000502:physiology*
D002352:Carrier Proteins; D051793:Hypoxia-Inducible Factor 1; D007093:Imidazoles; D053583:Interleukin-1beta; D008024:Ligands; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D000493:Allopurinol; D014969:Xanthine Oxidase; D020170:Caspase 1; C402365:resiquimod