The
ketone bodies β-hydroxybutyrate (BHB) and
acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of
ATP. BHB levels are elevated by
starvation,
caloric restriction, high-intensity exercise, or the low-
carbohydrate ketogenic diet. Prolonged fasting reduces
inflammation; however, the impact that
ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related
short-chain fatty acids butyrate and
acetate, suppresses activation of the NLRP3
inflammasome in response to
urate crystals,
ATP and lipotoxic
fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in
melanoma 2 (AIM2)
inflammasome and did not affect non-canonical caspase-11,
inflammasome activation. Mechanistically, BHB inhibits the NLRP3
inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or
starvation-regulated mechanisms like
AMP-activated protein kinase (AMPK),
reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3
inflammasome without undergoing oxidation in the TCA cycle, and independently of
uncoupling protein-2 (UCP2), sirtuin-2 (
SIRT2), the
G protein-coupled receptor GPR109A or hydrocaboxylic
acid receptor 2 (HCAR2). BHB reduces NLRP3
inflammasome-mediated
interleukin (IL)-1β and
IL-18 production in human monocytes. In vivo, BHB or a
ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as
Muckle-Wells syndrome,
familial cold autoinflammatory syndrome and
urate crystal-induced
peritonitis. Our findings suggest that the anti-inflammatory effects of
caloric restriction or
ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3
inflammasome.