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

Nature Medicine

Volumn 21, Issue 3, 2015, Pages 263-269

  Youm, Yun Hee ^a   Nguyen, Kim Y ^a   Grant, Ryan W ^b   Goldberg, Emily L ^a   Bodogai, Monica ^c   Kim, Dongin ^d   D'Agostino, Dominic ^e   Planavsky, Noah ^f   Lupfer, Christopher ^g   Kanneganti, Thirumala D ^g   Kang, Seokwon ^h   Horvath, Tamas L ^a   Fahmy, Tarek M ^d   Crawford, Peter A ⁱ   Biragyn, Arya ^c   Alnemri, Emad ^h   Dixit, Vishwa Deep ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b PURDUE UNIVERSITY   (United States)

^c NATIONAL INSTITUTE ON AGING   (United States)

^d Yale University   (United States)

^e UNIVERSITY OF SOUTH FLORIDA   (United States)

^f YALE UNIVERSITY   (United States)

^g ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^h THOMAS JEFFERSON UNIVERSITY   (United States)

ⁱ BURNHAM INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXYBUTYRIC ACID; ABSENT IN MELANOMA 2; ACETOACETIC ACID; ADENOSINE TRIPHOSPHATE; CASPASE 11; CRYOPYRIN; FATTY ACID; G PROTEIN COUPLED RECEPTOR; HYDROCABOXYLIC ACID RECEPTOR 2; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INFLAMMASOME; INTERLEUKIN 18; INTERLEUKIN 1BETA; INTERLEUKIN 1BETA CONVERTING ENZYME; REACTIVE OXYGEN METABOLITE; SIRTUIN 2; UNCLASSIFIED DRUG; UNCOUPLING PROTEIN 2; URATE; CARRIER PROTEIN; CIAS1 PROTEIN, MOUSE; NLRP3 PROTEIN, HUMAN; POTASSIUM;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOPHAGY; CITRIC ACID CYCLE; CONTROLLED STUDY; CYTOKINE RELEASE; ENZYME ACTIVATION; FAMILIAL COLD AUTOINFLAMMATORY SYNDROME; HUMAN; HUMAN CELL; INFLAMMATORY DISEASE; KETOGENIC DIET; MOUSE; MUCKLE WELLS SYNDROME; NONHUMAN; OXIDATION; PERITONITIS; POTASSIUM TRANSPORT; PRIORITY JOURNAL; ADULT; AGED; ANIMAL; ANTAGONISTS AND INHIBITORS; CINCA SYNDROME; DISEASE MODEL; DRUG EFFECTS; FEMALE; INFLAMMATION; MALE; METABOLISM; MONOCYTE; SECRETION (PROCESS);

3-HYDROXYBUTYRIC ACID; ADULT; AGED; ANIMALS; CARRIER PROTEINS; CASPASE 1; CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; INFLAMMASOMES; INFLAMMATION; INTERLEUKIN-18; INTERLEUKIN-1BETA; KETOGENIC DIET; MALE; MICE; MONOCYTES; POTASSIUM;

EID: 84924356420     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3804     Document Type: Article

References (36)

1. Newman, J.C. & Verdin, E. Ketone bodies as signaling metabolites. Trends Endocrinol. Metab. 25, 42-52 (2014).
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).
3. Shido, O., Nagasaka, T. & Watanabe, T. Blunted febrile response to intravenous endotoxin in starved rats. J. Appl. Physiol. 67, 963-969 (1989).
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).
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).
6. McGettrick, A.F. & O'Neill, L.A. How metabolism generates signals during innate immunity and inflammation. J. Biol. Chem. 288, 22893-22898 (2013).
7. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229-265 (2009).
8. Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 157, 1013-1022 (2014).
9. Wen, H., Miao, E.A. & Ting, J.P. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432-441 (2013).
10. Latz, E., Xiao, T.S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397-411 (2013).
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).
12. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179-188 (2011).
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).
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).
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).
16. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357-1361 (2010).
17. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408-415 (2011).
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).
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).
20. Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246-1249 (2013).
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).
22. Shimazu, T. et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211-214 (2013).
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).
24. Finn, P.F. & Dice, J.F. Ketone bodies stimulate chaperone-mediated autophagy. J. Biol. Chem. 280, 25864-25870 (2005).
25. + efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142-1153 (2013).
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).
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).
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).
29. Misawa, T. et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat. Immunol. 14, 454-460 (2013).
30. Lutas, A. & Yellen, G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 36, 32-40 (2013).
31. Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 156, 1193-1206 (2014).
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).
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).
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).
35. Brydges, S.D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875-887 (2009).
36. Anand, P.K. et al. NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488, 389-393 (2012).