title: The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.
abstract: 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.
authors: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Yun-Hee
authors: YH
authors: Youm
authors: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Kim Y
authors: KY
authors: Nguyen
authors: Department of Nutrition Sciences, Purdue University, West Lafayette, Indiana.
authors: Ryan W
authors: RW
authors: Grant
authors: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Emily L
authors: EL
authors: Goldberg
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health (NIH), Baltimore, Maryland, USA.
authors: Monica
authors: M
authors: Bodogai
authors: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
authors: Dongin
authors: D
authors: Kim
authors: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
authors: Dominic
authors: D
authors: D'Agostino
authors: Department of Geology and Geophysics, Yale University, New Haven, Connecticut, USA.
authors: Noah
authors: N
authors: Planavsky
authors: Department of Immunology, St. Jude Children's Hospital, Memphis, Tennessee, USA.
authors: Christopher
authors: C
authors: Lupfer
authors: Department of Immunology, St. Jude Children's Hospital, Memphis, Tennessee, USA.
authors: Thirumala D
authors: TD
authors: Kanneganti
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Seokwon
authors: S
authors: Kang
authors: Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Tamas L
authors: TL
authors: Horvath
authors: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
authors: Tarek M
authors: TM
authors: Fahmy
authors: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.
authors: Peter A
authors: PA
authors: Crawford
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health (NIH), Baltimore, Maryland, USA.
authors: Arya
authors: A
authors: Biragyn
authors: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors: Emad
authors: E
authors: Alnemri
authors: 1] Section of Comparative Medicine and Program on Integrative Cell Signaling and Neurobiology of Metabolism, Yale School of Medicine, New Haven, Connecticut, USA. [2] Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
authors: Vishwa Deep
authors: VD
authors: Dixit
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D020170:Caspase 1 / Q000187:drug effects*; D056587:Cryopyrin-Associated Periodic Syndromes; D055423:Diet, Ketogenic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors*; D007249:Inflammation; D020382:Interleukin-18; D053583:Interleukin-1beta / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020170:Caspase 1; D011188:Potassium; D020155:3-Hydroxybutyric Acid