α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Nature Immunology

Volumn 18, Issue 9, 2017, Pages 985-994

  Liu, Pu Ste ^a,b   Wang, Haiping ^a,b   Li, Xiaoyun ^a,b   Chao, Tung ^a,b   Teav, Tony ^a   Christen, Stefan ^c,d   DI Conza, Giusy ^a,b   Cheng, Wan Chen ^a,b   Chou, Chih Hung ^e   Vavakova, Magdalena ^a,b   Muret, Charlotte ^a,b   Debackere, Koen ^f   Mazzone, Massimiliano ^f   Huang, Hsien Da ^e   Fendt, Sarah Maria ^c,d   Ivanisevic, Julijana ^a   Ho, Ping Chih ^a,b  

^a UNIVERSITY OF LAUSANNE   (Switzerland)

^b Ludwig Lausanne Branch   (Switzerland)

^c Center for Cancer Biology (CCB)   (Belgium)

^d Katholieke Universiteit   (Belgium)

^e NATIONAL CHIAO TUNG UNIVERSITY   (Taiwan)

^f KU Leuven and University Hospitals Leuven and Leuven Cancer Institute   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2 OXOGLUTARIC ACID; ALPHA-KETOGLUTARIC ACID; FATTY ACID; GLUTAMINE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LIPOPOLYSACCHARIDE; SUCCINIC ACID;

ANIMAL; CHROMATIN IMMUNOPRECIPITATION; CITRIC ACID CYCLE; GENE EXPRESSION PROFILING; GENETIC EPIGENESIS; GLYCOLYSIS; IMMUNOLOGY; MACROPHAGE; MACROPHAGE ACTIVATION; METABOLISM; METABOLOMICS; MOUSE; NUCLEAR REPROGRAMMING; OXIDATION REDUCTION REACTION; OXIDATIVE PHOSPHORYLATION; PHENOTYPE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SEQUENCE ANALYSIS;

ANIMALS; CELLULAR REPROGRAMMING; CHROMATIN IMMUNOPRECIPITATION; CITRIC ACID CYCLE; EPIGENESIS, GENETIC; FATTY ACIDS; GENE EXPRESSION PROFILING; GLUTAMINE; GLYCOLYSIS; KETOGLUTARIC ACIDS; LIPOPOLYSACCHARIDES; MACROPHAGE ACTIVATION; MACROPHAGES; METABOLOMICS; MICE; NF-KAPPA B; OXIDATION-REDUCTION; OXIDATIVE PHOSPHORYLATION; PHENOTYPE; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; SEQUENCE ANALYSIS, RNA; SUCCINIC ACID;

EID: 85027878861     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3796     Document Type: Article

References (45)

1. Murray, P.J., et al. Macrophage activation and polarization: Nomenclature and experimental guidelines. Immunity 41, 14-20 (2014).
2. Ivashkiv, L.B. Epigenetic regulation of macrophage polarization and function. Trends Immunol. 34, 216-223 (2013).
3. Biswas, S.K., Lopez-Collazo, E. Endotoxin tolerance: New mechanisms, molecules and clinical significance. Trends Immunol. 30, 475-487 (2009).
4. Sawhney, S., Woo, P., Murray, K.J. Macrophage activation syndrome: A potentially fatal complication of rheumatic disorders. Arch. Dis. Child. 85, 421-426 (2001).
5. Ho, P.C., Tsui, Y.C., Feng, X., Greaves, D.R., Wei, L.N. NF-B-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat. Immunol. 13, 379-386 (2012).
6. O'Neill, L.A., Pearce, E.J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15-23 (2016).
7. O'Neill, L.A., Kishton, R.J., Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553-565 (2016).
8. Tannahill, G.M., et al. Succinate is an inflammatory signal that induces IL-1 through HIF-1. Nature 496, 238-242 (2013).
9. Liu, L., et al. Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1-dependent. Proc. Natl. Acad. Sci. USA 113, 1564-1569 (2016).
10. Mills, E.L., et al. Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages. Cell 167, 457-470.e413 (2016).
11. Huang, S.C., et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846-855 (2014).
12. Vats, D., et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 4, 13-24 (2006).
13. Covarrubias, A.J., et al. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. eLife 5, e11612 (2016).
14. Huang, S.C., et al. Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. Immunity 45, 817-830 (2016).
15. Jha, A.K., et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419-430 (2015).
16. Fendt, S.M., et al. Reductive glutamine metabolism is a function of the-ketoglutarate to citrate ratio in cells. Nat. Commun. 4, 2236 (2013).
17. Carey, B.W., Finley, L.W., Cross, J.R., Allis, C.D., Thompson, C.B. Intracellular-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413-416 (2015).
18. Bricker, D.K., et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 337, 96-100 (2012).
19. Ishii, M., et al. Epigenetic regulation of the alternatively activated macrophage phenotype. Blood 114, 3244-3254 (2009).
20. Satoh, T., et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936-944 (2010).
21. Kruidenier, L., et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404-408 (2012).
22. Platt, R.J., et al. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159, 440-455 (2014).
23. TeSlaa, T.-Ketoglutarate Accelerates the Initial Differentiation of Primed Human Pluripotent Stem Cells. Cell Metab. 24, 485-493 (2016).
24. Fraisl, P., Aragonés, J., Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat. Rev. Drug Discov. 8, 139-152 (2009).
25. Cummins, E.P., et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc. Natl. Acad. Sci. USA 103, 18154-18159 (2006).
26. Takeda, Y., et al. Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis. Nature 479, 122-126 (2011).
27. Rodríguez-Prados, J.C., et al. Substrate fate in activated macrophages: A comparison between innate, classic, and alternative activation. J. Immunol. 185, 605-614 (2010).
28. Shalova, I.N., et al. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1. Immunity 42, 484-498 (2015).
29. Su, X., et al. Interferon-regulates cellular metabolism and mRNA translation to potentiate macrophage activation. Nat. Immunol. 16, 838-849 (2015).
30. Cheng, S.C., et al. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat. Immunol. 17, 406-413 (2016).
31. Chen, J., Ivashkiv, L.B. IFN-A brogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling. Proc. Natl. Acad. Sci. USA 107, 19438-19443 (2010).
32. De Santa, F., et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J. 28, 3341-3352 (2009).
33. Pan, D., et al. Jmjd3-Mediated H3K27me3 Dynamics Orchestrate Brown Fat Development and Regulate White Fat Plasticity. Dev. Cell 35, 568-583 (2015).
34. Zhang, Q., et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525, 389-393 (2015).
35. Saeed, S., et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).
36. Arts, R.J., et al. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metab. 24, 807-819 (2016).
37. del Fresno, C., et al. Tumor cells deactivate human monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4. J. Immunol. 174, 3032-3040 (2005).
38. Hagemann, T., et al. "Re-educating" tumor-associated macrophages by targeting NF-kB. J. Exp. Med. 205, 1261-1268 (2008).
39. Mantovani, A., Sica, A. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231-237 (2010).
40. Wise, D.R., Thompson, C.B. Glutamine addiction: A new therapeutic target in cancer. Trends Biochem. Sci. 35, 427-433 (2010).
41. Altman, B.J., Stine, Z.E., Dang, C.V. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619-634 (2016).
42. Ye, D., Ma, S., Xiong, Y., Guan, K.L. R-2-hydroxyglutarate as the key effector of IDH mutations promoting oncogenesis. Cancer Cell 23, 274-276 (2013).
43. Black, J.C., Van Rechem, C., Whetstine, J.R. Histone lysine methylation dynamics: Establishment, regulation, and biological impact. Mol. Cell 48, 491-507 (2012).
44. Clever, D., et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166, 1117-1131.e14 (2016).
45. Christen, S., et al. Breast cancer-derived lung metastases show increased pyruvate carboxylase-dependent anaplerosis. Cell Rep. 17, 837-848 (2016).