51. β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares.
- Author
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Goldberg EL, Asher JL, Molony RD, Shaw AC, Zeiss CJ, Wang C, Morozova-Roche LA, Herzog RI, Iwasaki A, and Dixit VD
- Subjects
- Adolescent, Adult, Aged, Animals, Diet, Ketogenic adverse effects, Female, Humans, Inflammasomes metabolism, Inflammation drug therapy, Inflammation metabolism, Interleukin-1beta metabolism, Macrophages drug effects, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Middle Aged, Neutrophils metabolism, Rats, Uric Acid metabolism, Young Adult, 3-Hydroxybutyric Acid pharmacology, Gout drug therapy, Gout metabolism, Inflammasomes drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Neutrophils drug effects
- Abstract
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1β (IL-1β) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases β-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1β in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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