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Cell Rep. 2017 Feb 28;18(9):2077-2087. doi: 10.1016/j.celrep.2017.02.004.

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

Author information

1
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.
2
Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
3
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
4
Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520, USA.
5
Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden.
6
Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
7
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
8
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.

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.

KEYWORDS:

IL-1; NLRP3 inflammasome; aging; gout; inflammation; neutrophil; β-hydroxybutyrate

PMID:
28249154
PMCID:
PMC5527297
DOI:
10.1016/j.celrep.2017.02.004
[Indexed for MEDLINE]
Free PMC Article

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