期刊
CELL REPORTS
卷 18, 期 9, 页码 2077-2087出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.02.004
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资金
- US NIH [AG043608, P01AG051459, AR070811, AI105097]
- Glenn Foundation for Aging Research
- American Foundation of Aging Research (AFAR)
- American Heart Association (AHA)
- NIH T32 [AI007019-38, AI055403]
- Francis Trudeau Trainee Fellowship
- NIH/NIDDK [K08 DK082618, R01 DK101984-02]
- Yale Center for Clinical Investigation (YCCI)
- Hospital Research Unit (HRU) [DK045735]
- Yale Diabetes Research Center
- Clinical Translational Science Award from the National Center for Advancing Translational Sciences [UL1-RR-024139]
- Howard Hughes Medical Institute
- NIH [K24 AG042489, U19 AI089992, P30 AG21342]
- NIH Roadmap for Medical Research
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-1 beta (IL-1 beta) 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 beta-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-1 beta 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.
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