β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares

Abstract

Abstract Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. IL-1β produced by macrophages and neutrophils drives gouty flares that cause joint destruction, intense pain and fever. Small clinical trials have reported that IL-1R antagonists reduced pain in gout patients, but these biologicals are expensive and may compromise immune responses. Moreover, current treatment strategies for gout are limited in efficacy and do not specifically target the NLRP3 inflammasome. NLRP3 activation is regulated by numerous metabolic byproducts. However, metabolites that impact neutrophil inflammasome remain unknown. 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 outbred rats fed a ketogenic diet, BHB blocked NLRP3-dependent IL-1β secretion from neutrophils from both 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.