Summary
Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of NLRP3 inflammasome. Neutrophil-mediated production of 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 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-1β in neutrophils in 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.