β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares

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.

eTOC Blurb

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.