β-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares

Cell Rep. 2017 Feb 28;18(9):2077-2087. doi: 10.1016/j.celrep.2017.02.004.

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.

Keywords: IL-1; NLRP3 inflammasome; aging; gout; inflammation; neutrophil; β-hydroxybutyrate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Adolescent
  • Adult
  • Aged
  • Animals
  • Diet, Ketogenic / adverse effects
  • Female
  • Gout / drug therapy*
  • Gout / metabolism*
  • Humans
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Rats
  • Uric Acid / metabolism
  • Young Adult

Substances

  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Uric Acid
  • 3-Hydroxybutyric Acid