Background/Purpose: In gout, monosodium urate (MSU) crystals trigger acute inflammation. MSU has been reported to activate NLRP3 inflammasome via ROS-dependent pathways, which result in IL-1beta secretion and cell death. To date, we have shown that febuxostat, a potent inhibitor of xanthine oxidoreductase (XOR), inhibits crystal-induced IL-1beta secretion and cell death in activated macrophages. In this study, we examined its inhibitory mechanisms. Methods: Bone marrow-derived macrophages were primed, incubated with febuxostat and stimulated with MSU. IL-1beta in the supernatant, intracellular ATP, mitochondrial ROS and membrane potential were analyzed. Results: MSU treatment resulted in the production of mitochondrial ROS as well as IL-1beta secretion, and led to decreased intracellular ATP (iATP) levels and depolarization of mitochondrial membrane potential. All these intracellular mechanisms were inhibited by febuxostat. Accordingly, Mito-TEMPO, a mitochondria-targeted antioxidant, inhibited IL-1beta secretion by decreasing mitochondrial ROS production; in addition, artificially decreased iATP induced IL-1beta secretion and depolarization of membrane potential in activated macrophages. Conclusion: These results suggested that MSU induces IL-1beta and cell death via two pathways: 1) mitochondrial ROS formation, 2) iATP reduction and mitochondrial dysfunction. Both pathways can be inhibited by febuxostat, suggesting that XOR inhibition not only decreases uric acid level in the blood but also suppresses crystal-induced inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/febuxostat-inhibits-monosodium-urate-crystal-induced-il-1beta-secretion-and-cell-death-via-ros-and-intracellular-atp-dependent-pathways/