Febuxostat, a Xanthine Oxidoreductase Inhibitor, Decreases NLRP3-dependent Inflammation in Macrophages by Activating the Purine Salvage Pathway and Restoring Cellular Bioenergetics

Nomura, Johji; Kobayashi, Tsunefumi; So, Alexander; Busso, Nathalie

doi:10.1038/s41598-019-53965-x

Cited by 32 publications

(26 citation statements)

References 27 publications

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“…The concentration of febuxostat used in the present study was lower than clinical concentration. Since recent report suggested that febuxostat at highest concentration of 200 μM could suppress the NLRP3 inflammasome 37) , we need further study to clarify this point.…”

Section: Discussionmentioning

confidence: 93%

Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

Taufiq

Kuwabara

et al. 2020

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Background: When macrophages are primed by lipopolysaccharides, mono sodium urate (MSU) crystals activate NLRP 3 inflammasomes and promote IL-1β and IL-18 production after phagocytosis of MSU. It was previously reported that anti-IL-1β antibodies suppress symptoms of gout and the occurrence of cardiovascular disease. Thus, inhibition of NLRP3 inflammasomes, which produce IL-1β and IL-18, may be a novel therapeutic strategy against these diseases. Purpose: To reveal the effects of dotinurad, a selective urate reabsorption inhibitor, and other uric acid lowering agents on MSU crystalinduced activation of NLRP3 inflammasomes in macrophages. Methods: Activity of NLRP3 inflammasomes in J774 mouse macrophages was evaluated by quantifying secreted caspase-1 and IL-1β using a western blot and ELISA in both the absence and presence of dotinurad or other uric acid lowering agents. Results: MSU increased protein levels of caspase-1 and IL-1β. This effect was inhibited by a clinical concentration of dotinurad. Neither febuxostat nor allopurinol influenced the levels of caspase-1 and IL-1β, whereas benzbromarone decreased their levels. The inhibitory effects of dotinurad and other uric acid lowering agents on secretions of IL-1β from the macrophages were confirmed by ELISA. Conclusion: Dotinurad, a selective urate reabsorption inhibitor, suppresses MSU-induced activation of NLRP3 inflammasomes in macrophages.

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Section: Discussionmentioning

confidence: 93%

Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

Taufiq

Kuwabara

et al. 2020

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“…Therefore, mitochondria constitutively produce ROS. A recent study has reported that inhibition of xanthine oxide reductase (XDH/XO) by febuxostat causes the increment of intracellular ATP by purine salvage pathway and reduces the production of ROS from MRC under normoxic conditions [47]. Thus, febuxostat may affect the production and activation of MMPs by reducing ROS derived from MRC under normoxic conditions.…”

Section: Discussionmentioning

confidence: 99%

Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia

et al. 2020

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Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.

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“…Dihydrorhodamine (DHR) 123 was already reported to be used for evaluation of mitochondrial ROS production in different cell lines including platelets [27][28][29][30][31][32]. In this study, DHR123 was applied for the evaluation of mito-…”

Section: Analysis Of Intra-platelet Ros Generationmentioning

confidence: 99%

Collagen-dependent platelet dysfunction and its relevance to either mitochondrial ROS or cytosolic superoxide generation: a question about the quality and functional competence of long-stored platelets

et al. 2020

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Background: Upon vascular damage, the exposed subendothelial matrix recruits circulating platelets to site of injury while inducing their firm adhesion mainly via GPVI-collagen interaction. GPVI also supports aggregatory and pro-coagulant functions in arterial shear rate even on the matrix other than collagen. Reactive oxygen species (ROS) modulate these stages of thrombosis; however augmented oxidant stress also disturbs platelet functions. Storeddependent platelet lesion is associated with the increasing levels of ROS. Whether ROS accumulation is also relevant to collagen-dependent platelet dysfunction is the main interest of this study. Methods: Fresh PRP-PCs (platelet concentrates) were either stimulated with potent ROS-inducers PMA and CCCP or stored for 5 days. Intra-platelet superoxide (O 2 −−) or mitochondrial-ROS and GPVI expression were detected by flowcytometery. GPVI shedding, platelet aggregation and spreading/adhesion to collagen were analyzed by western blot, aggregometry and fluorescence-microscopy, respectively. Results: Mitochondrial-ROS levels in 5 days-stored PCs were comparable to those induced by mitochondrial uncoupler, CCCP while O 2 −− generations were higher than those achieved by PMA. Shedding levels in 5 daysstored PCs were higher than those induced by these potent stimuli. GPVI expressions were reduced comparably in CCCP treated and 5 days-stored PCs. Platelet adhesion was also diminished during storage while demonstrating significant reverse correlation with GPVI shedding. However, only firm adhesion (indicated by platelets spreading or adhesion surface area) was relevant to GPVI expression. Platelet adhesion and aggregation also showed reverse correlations with both O2 −− and mitochondrial-ROS formations; nonetheless mitochondrial-ROS was only relevant to firm adhesion.

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Febuxostat, a Xanthine Oxidoreductase Inhibitor, Decreases NLRP3-dependent Inflammation in Macrophages by Activating the Purine Salvage Pathway and Restoring Cellular Bioenergetics

Cited by 32 publications

References 27 publications

Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia

Collagen-dependent platelet dysfunction and its relevance to either mitochondrial ROS or cytosolic superoxide generation: a question about the quality and functional competence of long-stored platelets

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