β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares

• Published in: Cell reports (Cambridge) Vol. 18; no. 9; pp. 2077 - 2087
• Main Authors: Goldberg, Emily L., Asher, Jennifer L., Molony, Ryan D., Shaw, Albert C., Zeiss, Caroline J., Wang, Chao, Morozova-Roche, Ludmilla A., Herzog, Raimund I., Iwasaki, Akiko, Dixit, Vishwa Deep
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.02.2017; Elsevier
• Subjects: 3-Hydroxybutyric Acid - pharmacology; Adolescent; Adult; Aged; aging; Animals; Diet, Ketogenic - adverse effects; Female; gout; Gout - drug therapy; Gout - metabolism; Humans; IL-1; Inflammasomes - drug effects; Inflammasomes - metabolism; inflammation; Inflammation - drug therapy; Inflammation - metabolism; Interleukin-1beta - metabolism; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; neutrophil; Neutrophils - drug effects; Neutrophils - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Rats; Uric Acid - metabolism; Young Adult; β-hydroxybutyrate; inflammation; IL-1; gout; β-hydroxybutyrate; aging; NLRP3 inflammasome; neutrophil
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.004

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. [Display omitted] •Inflammation and joint pathology during gout flare is prevented by ketogenic diet•BHB inhibits IL-1β secretion from neutrophils•Ketogenic diet and BHB inhibit NLRP3 activation in aged neutrophils•BHB inhibits both priming and assembly steps of NLRP3 activation in neutrophils NLRP3 inflammasome activation in macrophages and neutrophils drives painful inflammation during gout. Goldberg et al. report that ketogenic diet prevents systemic inflammation and joint damage in a rat model of gouty flare. Mechanistically, the ketone body β-hydroxybutyrate, the most abundant ketone in vivo, inhibits NLRP3/caspase-1-dependent IL-1β secretion from neutrophils.