Inhibition of xanthine oxidoreductase with febuxostat, but not allopurinol, prevents inflammasome assembly and IL-1β release.

Xanthine oxidoreductase (XOR) inhibitors are used to treat gout, inhibiting uric acid production, which causes clinical symptoms. Commonly used XOR inhibitors are the small molecule febuxostat (Fbx) and the purine analogue allopurinol (Allo). Recent studies show that XOR inhibitors can reduce mature interleukin (IL)-1β production by activated macrophages. This effect is not due to reduced uric acid crystal formation, which can induce NLRP3 inflammasome activation, but an independent effect. Fbx and Allo have been used interchangeably in in vitro studies to highlight the role of XOR in pro-inflammatory macrophage function. Here, we analysed the effects of Fbx and Allo on pro-inflammatory macrophage signatures. Both XOR inhibitors maintain pro-inflammatory macrophage metabolic and phenotypic hallmarks. However, only Fbx reduces the activity of caspase-1 and the release of IL-1β by preventing inflammasome assembly in macrophages isolated from both mice and humans. Our study identified an Fbx-specific reduction in IL-1β production, which could be used clinically to reduce the deleterious effects of macrophage-derived IL-1β.