(01-03-15) The ketone metabolite â-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.

Youm YH1, Nguyen KY1, Grant RW2, Goldberg EL1, Bodogai M3, Kim D4, D'Agostino D5, Planavsky N6, Lupfer C7, Kanneganti TD7,Kang S8, Horvath TL1, Fahmy TM4, Crawford PA9, Biragyn A3, Alnemri E8, Dixit VD10.
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Abstract
The ketone bodies â-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)-1â and IL-18 production in human monocytes. In vivo, BHBor a ketogenic diet attenuates caspase-1 activation and IL-1â 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.

SOURCE: Nat Med. 2015 Feb 16. doi: 10.1038/nm.3804. [Epub ahead of print]

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