Febuxostat, a Xanthine Oxidoreductase Inhibitor, Decreases NLRP3-dependent Inflammation in Macrophages by Activating the Purine Salvage Pathway and Restoring Cellular Bioenergetics.
Details
Serval ID
serval:BIB_7553638C2E17
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Febuxostat, a Xanthine Oxidoreductase Inhibitor, Decreases NLRP3-dependent Inflammation in Macrophages by Activating the Purine Salvage Pathway and Restoring Cellular Bioenergetics.
Journal
Scientific reports
ISSN
2045-2322 (Electronic)
ISSN-L
2045-2322
Publication state
Published
Issued date
21/11/2019
Peer-reviewed
Oui
Volume
9
Number
1
Pages
17314
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Abstract
The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome mediates caspase-1 activation and IL-1β processing and is implicated in autoinflammatory as well as other chronic inflammatory diseases. Recent studies have demonstrated that xanthine oxidoreductase (XOR) inhibition attenuated IL-1β secretion in activated macrophages, but the detailed mechanism of inhibition remains unclear. In this study, we report that febuxostat, an inhibitor of XOR, suppressed NLRP3 inflammasome-mediated IL-1β secretion and cell death by two mechanisms: in a mitochondrial ROS (mitoROS)-dependent and mitoROS-independent manner. MitoROS-independent effects of febuxostat were mediated by an increase of intracellular ATP and improved mitochondrial energetics via the activation of purine salvage pathway. Our findings suggest that cellular bioenergetics are important in regulating NLRP3 activation, and XOR inhibition may be clinically relevant in NLRP3-related inflammatory diseases.
Keywords
Animals, Anti-Inflammatory Agents/pharmacology, Anti-Inflammatory Agents/therapeutic use, Cells, Cultured, Energy Metabolism/drug effects, Energy Metabolism/immunology, Febuxostat/pharmacology, Febuxostat/therapeutic use, Humans, Inflammasomes/drug effects, Inflammasomes/immunology, Inflammasomes/metabolism, Inflammation/drug therapy, Inflammation/immunology, Macrophages/drug effects, Macrophages/immunology, Macrophages/metabolism, Mice, Mitochondria/drug effects, Mitochondria/metabolism, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Primary Cell Culture, Purines/metabolism, Reactive Oxygen Species/metabolism, Xanthine Dehydrogenase/antagonists & inhibitors, Xanthine Dehydrogenase/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
15/12/2019 16:41
Last modification date
23/04/2024 7:12