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The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease


The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP1. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet2. 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 unknown2,3,4,5,6. 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.

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Figure 1: BHB specifically inhibits the NLRP3 inflammasome.
Figure 2: BHB inhibits the NLRP3 inflammasome independently of Gpr109a and starvation-regulated mechanisms.
Figure 3: BHB inhibits ASC oligomerization and speck formation without undergoing mitochondrial oxidation.
Figure 4: BHB suppresses NLRP3-mediated inflammatory disease in vivo and inflammasome activation in human monocytes.


  1. 1

    Newman, J.C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42–52 (2014).

    CAS  Article  Google Scholar 

  2. 2

    Cotter, D.G., Schugar, R.C. & Crawford, P.A. Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–H1076 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Shido, O., Nagasaka, T. & Watanabe, T. Blunted febrile response to intravenous endotoxin in starved rats. J. Appl. Physiol. 67, 963–969 (1989).

    CAS  Article  Google Scholar 

  4. 4

    Johnson, J.B. et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic. Biol. Med. 42, 665–674 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Mercken, E.M. et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 12, 645–651 (2013).

    CAS  Article  Google Scholar 

  6. 6

    McGettrick, A.F. & O'Neill, L.A. How metabolism generates signals during innate immunity and inflammation. J. Biol. Chem. 288, 22893–22898 (2013).

    CAS  Article  Google Scholar 

  7. 7

    Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).

    CAS  Article  Google Scholar 

  9. 9

    Wen, H., Miao, E.A. & Ting, J.P. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432–441 (2013).

    CAS  Article  Google Scholar 

  10. 10

    Latz, E., Xiao, T.S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).

    CAS  Article  Google Scholar 

  11. 11

    Franchi, L., Eigenbrod, T., Muñoz-Planillo, R. & Nuñez, G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241–247 (2009).

    CAS  Article  Google Scholar 

  12. 12

    Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Masters, S.L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Heneka, M.T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

    CAS  Article  Google Scholar 

  15. 15

    Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408–415 (2011).

    CAS  Article  Google Scholar 

  18. 18

    Shaw, P.J. et al. Cutting edge: critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. J. Immunol. 184, 4610–4614 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Youm, Y.H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013).

    CAS  Article  Google Scholar 

  20. 20

    Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Hagar, J.A., Powell, D.A., Aachoui, Y., Ernst, R.K. & Miao, E.A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).

    CAS  Article  Google Scholar 

  23. 23

    Laeger, T., Pöhland, R., Metges, C.C. & Kuhla, B. The ketone body β-hydroxybutyric acid influences agouti-related peptide expression via AMP-activated protein kinase in hypothalamic GT1–7 cells. J. Endocrinol. 213, 193–203 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Finn, P.F. & Dice, J.F. Ketone bodies stimulate chaperone-mediated autophagy. J. Biol. Chem. 280, 25864–25870 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Muñoz-Planillo, R. et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).

    Article  Google Scholar 

  26. 26

    Taggart, A.K. et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    CAS  Article  Google Scholar 

  28. 28

    Cotter, D.G., Ercal, B., d'Avignon, D.A., Dietzen, D.J. & Crawford, P.A. Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth. J. Biol. Chem. 288, 19739–19749 (2013).

    CAS  Article  Google Scholar 

  29. 29

    Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454–460 (2013).

    CAS  Article  Google Scholar 

  30. 30

    Lutas, A. & Yellen, G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 36, 32–40 (2013).

    CAS  Article  Google Scholar 

  31. 31

    Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 156, 1193–1206 (2014).

    CAS  Article  Google Scholar 

  32. 32

    Yu, J.W. et al. Cryopyrin and pyrin activate caspase-1, but not NF-κB, via ASC oligomerization. Cell Death Differ. 13, 236–249 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Demento, S.L., Siefert, A.L., Bandyopadhyay, A., Sharp, F.A. & Fahmy, T.M. Pathogen-associated molecular patterns on biomaterials: a paradigm for engineering new vaccines. Trends Biotechnol. 29, 294–306 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Brydges, S.D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887 (2009).

    CAS  Article  Google Scholar 

  36. 36

    Anand, P.K. et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488, 389–393 (2012).

    CAS  Article  Google Scholar 

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We thank M. Koch, Y. Kui, P. Chang and D. Albarado for technical assistance, and V. M. Dixit (Genentech) and R. Medzhitov (Yale School of Medicine) for helpful discussions and for providing knockout mice. Salmonella typhimurium and Francisella tularensis (U112) were provided by D. Monack (Stanford University School of Medicine) and J. Teale (University of Texas at San Antonio). M.B. and A.B. were supported by the National Institute on Aging–Intramural Research Program. D.D'A. was supported by the Office of Naval Research (ONR) Grant N000141310062. V.D.D. was supported in part by the grants from National Institutes of Health (AG043608, AG31797, DK090556 and AI105097).

Author information




Y. H.Y. and K.Y.N. designed and conducted the majority of in vitro and all in vivo experiments, analyzed and interpreted the data, and participated in writing the manuscript. R.W.G. participated in design and conduct of inflammasome activation experiments. E.L.G. performed ASC speck and neutrophil assays. M.B. and A.B. performed the human monocytes experiments. D.K. and T.M.F. synthesized the BHB–nanolipogels and conducted control experiments to determine the dose response. D.D'A. formulated the ketone diester diet. N.P. conducted the ICP-MS experiments to determine K+ efflux. C.L. and T.D.K. conducted the F. tularensis and S. typhimurium infection experiments. T.L.H. designed the experiments and provided essential reagents for experiments involving mitochondrial ROS and UCP2. P.A.C. generated the macrophage-specific, Scot-deficient mice and contributed to experiment design. S.K. and E.A. designed and conducted the ASC oligomerization experiments. V.D.D. conceived and supervised the project, interpreted the data, and wrote the manuscript.

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Correspondence to Vishwa Deep Dixit.

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The authors declare no competing financial interests.

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Youm, YH., Nguyen, K., Grant, R. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nat Med 21, 263–269 (2015).

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