Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease

By Y. Youm, K. Nguyen, R. Grant, Emily L. Goldberg, M. Bodogai, Dongin Kim, D. D'Agostino, N. Planavsky, Christopher R. Lupfer, T. Kanneganti and 7 more. Nature Medicine, 2015

1,602 citations recorded by the source corpus.

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.

Subfields: Biological Psychiatry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/44fcb734ea5d23d4738e0bf63047a89abeaed6ce

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Citations in the corpus

Metabolic Control of Longevity. (2016, background): “Interestingly, ketone bodies that rise upon fasting (i.e., b-hydroxybutyrate) potently inhibit the NLRP3 inflammasome (Youm et al., 2015), proving another link between CR and lifespan extension.”
Metabolic Instruction of Immunity (2017, positive): “Interestingly, specific ketone bodies have been shown to minimize inflammation in other instances by blocking NLRP3 inflammasome activation in bone marrow-derived macrophages and human monocytes (Youm et al., 2015).”
Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, methodology): “…3,4-methylenedioxy-β-nitrostyrene (MNS), parthenolide, BAY 11-7082, INF39, and MCC950 (Juliana et al., 2010; He et al., 2014; Honda et al., 2014; Youm et al., 2015; Daniels et al., 2016; Greaney et al., 2016; Cocco et al., 2017), have been developed, but there is no evidence showing that…”
NLRP3 inflammasome and its inhibitors: a review (2015, background): “Youm et al. (2015) discovered that the ketone metabolite β-hydroxybutyrate (BHB), but not acetoacetate or the shortchain fatty acids butyrate and acetate, reduced IL-1β, and IL-18 production by the NLRP3 inflammasome in human monocytes.”
Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics (2017, methodology): “It is intriguing that macrophage GPR109A is required to exert a neuroprotective effect in an ischemic stroke model (Rahman et al., 2014), but the ability of bOHB to inhibit the NLRP3 inflammasome in bone marrow-derived macrophages is GPR109A independent (Youm et al., 2015).”
Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. (2016, neutral): “Moreover, pharmacologically targeting the NLRP3 inflammasome with its antagonists or inhibitors, such as β-hydroxybutyrate (Youm et al., 2015), prostaglandin E2 (Sokolowska et al., 2015), levornidazole (Wang et al., 2015d), DPP-4 inhibitors (Dai et al., 2014), ellagic acid (Tang et al., 2015),…”