title: β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares.
abstract: 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.
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Goldberg
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Asher
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Molony
authors.affiliation: Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Zeiss
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, 901 87 Umeå, Sweden.
authors.forename: Ludmilla A
authors.initials: LA
authors.lastname: Morozova-Roche
authors.affiliation: Section of Endocrinology and Metabolism, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Raimund I
authors.initials: RI
authors.lastname: Herzog
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Section of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: vishwa.dixit@yale.edu.
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D055423:Diet, Ketogenic / Q000009:adverse effects; D005260:Female; D006073:Gout / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D014527:Uric Acid / Q000378:metabolism; D055815:Young Adult
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014527:Uric Acid; D020155:3-Hydroxybutyric Acid
keywords: IL-1; NLRP3 inflammasome; aging; gout; inflammation; neutrophil; β-hydroxybutyrate