β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares.

Autor:	Goldberg EL; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Asher JL; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA., Molony RD; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA., Shaw AC; Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520, USA., Zeiss CJ; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA., Wang C; Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden., Morozova-Roche LA; Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden., Herzog RI; Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, CT 06520, USA., Iwasaki A; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA., Dixit VD; Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: vishwa.dixit@yale.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2017 Feb 28; Vol. 18 (9), pp. 2077-2087.
DOI:	10.1016/j.celrep.2017.02.004
Abstrakt:	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.)
Databáze:	MEDLINE
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