Krebs Cycle Reborn in Macrophage Immunometabolism

Literature Cited

1. 1. 

   Janeway CA Jr., Medzhitov R. 2002. Innate immune recognition. Annu. Rev. Immunol. 20:197–216
   [Google Scholar]
2. 2. 

   Seong S-Y, Matzinger P. 2004. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat. Rev. Immunol. 4:6469–78
   [Google Scholar]
3. 3. 

   Kelly B, O'Neill LA. 2015. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25:771–84
   [Google Scholar]
4. 4. 

   Diskin C, Palsson-McDermott EM. 2018. Metabolic modulation in macrophage effector function. Front. Immunol. 9:270
   [Google Scholar]
5. 5. 

   Krebs HA, Johnson WA. 1980. The role of citric acid in intermediate metabolism in animal tissues. FEBS Lett 117:Suppl.K1–10
   [Google Scholar]
6. 6. 

   Owen OE, Kalhan SC, Hanson RW 2002. The key role of anaplerosis and cataplerosis for citric acid cycle function. J. Biol. Chem. 277:30409–12
   [Google Scholar]
7. 7. 

   Kornberg H. 2000. Krebs and his trinity of cycles. Nat. Rev. Mol. Cell Biol. 1:225–28
   [Google Scholar]
8. 8. 

   Buchanan BB, Arnon DI. 1990. A reverse KREBS cycle in photosynthesis: consensus at last. Photosynth. Res. 24:47–53
   [Google Scholar]
9. 9. 

   Saraste M. 1999. Oxidative phosphorylation at the fin de siècle. Science 283:1488–93
   [Google Scholar]
10. 10. 

    Schultz BE, Chan SI. 2001. Structures and proton-pumping strategies of mitochondrial respiratory enzymes. Annu. Rev. Biophys. Biomol. Struct. 30:23–65
    [Google Scholar]
11. 11. 

    Mulkidjanian AY. 2009. On the origin of life in the zinc world. 1. Photosynthesizing, porous edifices built of hydrothermally precipitated zinc sulfide as cradles of life on Earth. Biol. Direct. 4:26
    [Google Scholar]
12. 12. 

    Remington SJ. 1992. Structure and mechanism of citrate synthase. Curr. Top. Cell Regul. 33:209–29
    [Google Scholar]
13. 13. 

    Lloyd SJ, Lauble H, Prasad GS, Stout CD 1999. The mechanism of aconitase: 1.8 Å resolution crystal structure of the S642A:citrate complex. Protein Sci 8:2655–62
    [Google Scholar]
14. 14. 

    Ma T, Peng Y, Huang W, Liu Y, Ding J 2017. The β and γ subunits play distinct functional roles in the α₂βγ heterotetramer of human NAD-dependent isocitrate dehydrogenase. Sci. Rep. 7:41882
    [Google Scholar]
15. 15. 

    Sheu KF, Blass JP. 1999. The alpha-ketoglutarate dehydrogenase complex. Ann. N. Y. Acad. Sci. 893:61–78
    [Google Scholar]
16. 16. 

    Johnson JD, Muhonen WW, Lambeth DO 1998. Characterization of the ATP- and GTP-specific succinyl-CoA synthetases in pigeon: The enzymes incorporate the same α-subunit. J. Biol. Chem. 273:27573–79
    [Google Scholar]
17. 17. 

    Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H et al. 2003. Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299:700–4
    [Google Scholar]
18. 18. 

    Rose IA. 1998. How fumarase recycles after the malate → fumarate reaction: insights into the reaction mechanism. Biochemistry 37:17651–58
    [Google Scholar]
19. 19. 

    Chapman AD, Cortes A, Dafforn TR, Clarke AR, Brady RL 1999. Structural basis of substrate specificity in malate dehydrogenases: crystal structure of a ternary complex of porcine cytoplasmic malate dehydrogenase, α-ketomalonate and tetrahydoNAD. J. Mol. Biol. 285:703–12
    [Google Scholar]
20. 20. 

    Ruprecht JJ, Kunji ER. 2019. Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier. Curr. Opin. Struct. Biol. 57:135–44
    [Google Scholar]
21. 21. 

    Capitanio D, Fania C, Torretta E, Vigano A, Moriggi M et al. 2017. TCA cycle rewiring fosters metabolic adaptation to oxygen restriction in skeletal muscle from rodents and humans. Sci. Rep. 7:9723
    [Google Scholar]
22. 22. 

    Costello LC, Franklin R, Stacey R 1976. Mitochondrial isocitrate dehydrogenase and isocitrate oxidation of rat ventral prostate. Enzyme 21:495–506
    [Google Scholar]
23. 23. 

    Costello LC, Fadika G, Franklin R 1978. Citrate and isocitrate utilization by rat ventral prostate mitochondria. Enzyme 23:176–81
    [Google Scholar]
24. 24. 

    Costello LC, Franklin RB. 2016. A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch. Biochem. Biophys. 611:100–12
    [Google Scholar]
25. 25. 

    Costello LC, Liu Y, Franklin RB, Kennedy MC 1997. Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J. Biol. Chem. 272:28875–81
    [Google Scholar]
26. 26. 

    Costello LC, Franklin RB. 2002. Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm. Metab. Res. 34:417–24
    [Google Scholar]
27. 27. 

    Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF et al. 2013. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–42
    [Google Scholar]
28. 28. 

    Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y et al. 2015. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42:419–30
    [Google Scholar]
29. 29. 

    O'Neill LA. 2015. A broken Krebs cycle in macrophages. Immunity 42:393–94
    [Google Scholar]
30. 30. 

    Bailey JD, Diotallevi M, Nicol T, McNeill E, Shaw A et al. 2019. Nitric oxide modulates metabolic remodeling in inflammatory macrophages through TCA cycle regulation and itaconate accumulation. Cell Rep 28:1218–30.e7
    [Google Scholar]
31. 31. 

    De Souza D, Achuthan A, Lee M, Binger K, Lee M et al. 2019. Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages. J. Clin. Investig. 129:104239–44
    [Google Scholar]
32. 32. 

    Utaisincharoen P, Anuntagool N, Arjcharoen S, Limposuwan K, Chaisuriya Psirisinha S 2004. Induction of iNOS expression and antimicrobial activity by interferon (IFN)-β is distinct from IFN-γ in Burkholderia pseudomallei-infected mouse macrophages. Clin. Exp. Immunol. 136:2277–83
    [Google Scholar]
33. 33. 

    Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC et al. 2016. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291:14274–84
    [Google Scholar]
34. 34. 

    Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE et al. 2016. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24:158–66
    [Google Scholar]
35. 35. 

    Seim GL, Britt EC, John SV, Yeo FJ, Johnson AR et al. 2019. Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation. Nat. Metab. 1:731–42
    [Google Scholar]
36. 36. 

    Hiromasa Y, Fujisawa T, Aso Y, Roche TE 2004. Organization of the cores of the mammalian pyruvate dehydrogenase complex formed by E2 and E2 plus the E3-binding protein and their capacities to bind the E1 and E3 components. J. Biol. Chem. 279:86921–33
    [Google Scholar]
37. 37. 

    Izard T, Aevarsson A, Allen MD, Westphal AH, Perham RN et al. 1999. Principles of quasi-equivalence and Euclidean geometry govern the assembly of cubic and dodecahedral cores of pyruvate dehydrogenase complexes. PNAS 96:41240–45
    [Google Scholar]
38. 38. 

    McCartney RG, Rice JE, Sanderson SJ, Bunik V, Lindsay H, Lindsay JG 1998. Subunit interactions in the mammalian α-ketoglutarate dehydrogenase complex: evidence for direct association of the α-ketoglutarate dehydrogenase and dihydrolipoamide dehydrogenase components. J. Biol. Chem. 273:3724158–64
    [Google Scholar]
39. 39. 

    O'Neill LA, Kishton RJ, Rathmell J 2016. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16:553–65
    [Google Scholar]
40. 40. 

    Wang F, Zhang S, Vuckovic I, Jeon R, Lerman A et al. 2018. Glycolytic stimulation is not a requirement for M2 macrophage differentiation. Cell Metab 28:463–75.e4
    [Google Scholar]
41. 41. 

    Nelson VL, Nguyen HCB, Garcia-Canaveras JC, Briggs ER, Ho WY et al. 2018. PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes Dev 32:1035–44
    [Google Scholar]
42. 42. 

    Mills EL, Kelly B, Logan A, Costa ASH, Varma M et al. 2016. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167:457–70.e13
    [Google Scholar]
43. 43. 

    Keiran N, Ceperuelo-Mallafre V, Calvo E, Hernandez-Alvarez MI, Ejarque M et al. 2019. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat. Immunol. 20:581–92
    [Google Scholar]
44. 44. 

    Park J, Chen Y, Tishkoff DX, Peng C, Tan M et al. 2013. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50:919–30
    [Google Scholar]
45. 45. 

    Liu PS, Wang H, Li X, Chao T, Teav T et al. 2017. α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18:985–94
    [Google Scholar]
46. 46. 

    Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S et al. 2016. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24:807–19
    [Google Scholar]
47. 47. 

    Corcoran SE, O'Neill LA. 2016. HIF1α and metabolic reprogramming in inflammation. J. Clin. Investig. 126:3699–707
    [Google Scholar]
48. 48. 

    Semenza GL, Wang GL. 1992. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12:5447–54
    [Google Scholar]
49. 49. 

    Semenza GL. 2009. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology 24:97–106
    [Google Scholar]
50. 50. 

    Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J et al. 2001. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54
    [Google Scholar]
51. 51. 

    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC et al. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–75
    [Google Scholar]
52. 52. 

    Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG et al. 2005. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7:77–85
    [Google Scholar]
53. 53. 

    Kietzmann T, Gorlach A. 2005. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin. Cell Dev. Biol. 16:474–86
    [Google Scholar]
54. 54. 

    Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT 2008. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol. Cell. Biol. 28:718–31
    [Google Scholar]
55. 55. 

    Hagen T. 2012. Oxygen versus reactive oxygen in the regulation of HIF-1α: the balance tips. Biochem. Res. Int. 2012:436981
    [Google Scholar]
56. 56. 

    Kelly B, Tannahill GM, Murphy MP, O'Neill LA 2015. Metformin inhibits the production of reactive oxygen species from NADH:ubiquinone oxidoreductase to limit induction of interleukin-1β (IL-1β) and boosts interleukin-10 (IL-10) in lipopolysaccharide (LPS)-activated macrophages. J. Biol. Chem. 290:20348–59
    [Google Scholar]
57. 57. 

    Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY et al. 2014. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515:431–35
    [Google Scholar]
58. 58. 

    Jin Z, Wei W, Yang M, Du Y, Wan Y 2014. Mitochondrial complex I activity suppresses inflammation and enhances bone resorption by shifting macrophage-osteoclast polarization. Cell Metab 20:483–98
    [Google Scholar]
59. 59. 

    Garaude J, Acin-Perez R, Martinez-Cano S, Enamorado M, Ugolini M et al. 2016. Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense. Nat. Immunol. 17:1037–45
    [Google Scholar]
60. 60. 

    Cameron AM, Castoldi A, Sanin DE, Flachsmann LJ, Field CS et al. 2019. Inflammatory macrophage dependence on NAD⁺ salvage is a consequence of reactive oxygen species-mediated DNA damage. Nat. Immunol. 20:420–32
    [Google Scholar]
61. 61. 

    Du J, Zhou Y, Su X, Yu JJ, Khan S et al. 2011. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334:806–9
    [Google Scholar]
62. 62. 

    Wang F, Wang K, Xu W, Zhao S, Ye D et al. 2017. SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice. Cell Rep 19:2331–44
    [Google Scholar]
63. 63. 

    Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ et al. 2015. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab 21:65–80 Erratum. 2015. Cell Metab. 21:347
    [Google Scholar]
64. 64. 

    Xiao M, Yang H, Xu W, Ma S, Lin H et al. 2012. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 26:1326–38 Erratum. 2015. Genes Dev. 29:887
    [Google Scholar]
65. 65. 

    Liu Z, Gan L, Zhang T, Ren Q, Sun C 2018. Melatonin alleviates adipose inflammation through elevating α-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice. J. Pineal Res. 64:e12455
    [Google Scholar]
66. 66. 

    Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S et al. 2014. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345:1250684
    [Google Scholar]
67. 67. 

    Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A et al. 2014. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345:1251086
    [Google Scholar]
68. 68. 

    He W, Miao FJ, Lin DC, Schwandner RT, Wang Z et al. 2004. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429:188–93
    [Google Scholar]
69. 69. 

    Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J et al. 2016. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 213:1655–62
    [Google Scholar]
70. 70. 

    Kim S, Hwang J, Xuan J, Jung YH, Cha HS, Kim KH 2014. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis. PLOS ONE 9:e97501
    [Google Scholar]
71. 71. 

    van Diepen JA, Robben JH, Hooiveld GJ, Carmone C, Alsady M et al. 2017. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia 60:1304–13
    [Google Scholar]
72. 72. 

    Peruzzotti-Jametti L, Bernstock JD, Vicario N, Costa ASH, Kwok CK et al. 2018. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell 22:355–68.e13
    [Google Scholar]
73. 73. 

    Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N et al. 2013. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. PNAS 110:7820–25
    [Google Scholar]
74. 74. 

    Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA et al. 2011. The mitochondrial citrate carrier: a new player in inflammation. Biochem. J. 438:433–36
    [Google Scholar]
75. 75. 

    Infantino V, Iacobazzi V, Palmieri F, Menga A 2013. ATP-citrate lyase is essential for macrophage inflammatory response. Biochem. Biophys. Res. Commun. 440:105–11
    [Google Scholar]
76. 76. 

    Meiser J, Kramer L, Sapcariu SC, Battello N, Ghelfi J et al. 2016. Pro-inflammatory macrophages sustain pyruvate oxidation through pyruvate dehydrogenase for the synthesis of itaconate and to enable cytokine expression. J. Biol. Chem. 291:3932–46
    [Google Scholar]
77. 77. 

    Denko NC. 2008. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8:705–13
    [Google Scholar]
78. 78. 

    Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB 2009. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324:1076–80
    [Google Scholar]
79. 79. 

    Carroll RG, Zasłona Z, Galván-Peña S, Koppe EL, Sévin DC et al. 2018. An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation. J. Biol. Chem. 293:5509–21
    [Google Scholar]
80. 80. 

    Wei X, Song H, Yin L, Rizzo MG, Sidhu R et al. 2016. Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539:294–98
    [Google Scholar]
81. 81. 

    Cader MZ, Boroviak K, Zhang Q, Assadi G, Kempster SL et al. 2016. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat. Immunol. 17:1046–56
    [Google Scholar]
82. 82. 

    Daskalaki MG, Tsatsanis C, Kampranis SC 2018. Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses. J. Cell Physiol. 233:6495–507
    [Google Scholar]
83. 83. 

    Kurdistani SK, Grunstein M. 2003. Histone acetylation and deacetylation in yeast. Nat. Rev. Mol. Cell Biol. 4:276–84
    [Google Scholar]
84. 84. 

    Feng D, Sangster-Guity N, Stone R, Korczeniewska J, Mancl ME et al. 2010. Differential requirement of histone acetylase and deacetylase activities for IRF5-mediated proinflammatory cytokine expression. J. Immunol. 185:6003–12
    [Google Scholar]
85. 85. 

    Hu L, Yu Y, Huang H, Fan H, Yin C et al. 2016. Epigenetic regulation of interleukin 6 by histone acetylation in macrophages and its role in paraquat-induced pulmonary fibrosis. Front. Immunol. 7:696
    [Google Scholar]
86. 86. 

    Moores RC, Brilha S, Schutgens F, Elkington PT, Friedland JS 2017. Epigenetic regulation of matrix metalloproteinase-1 and -3 expression in Mycobacterium tuberculosis infection. Front. Immunol. 8:602
    [Google Scholar]
87. 87. 

    Lu J, Sun H, Wang X, Liu C, Xu X et al. 2005. Interleukin-12 p40 promoter activity is regulated by the reversible acetylation mediated by HDAC1 and p300. Cytokine 31:46–51
    [Google Scholar]
88. 88. 

    Wang B, Rao YH, Inoue M, Hao R, Lai CH et al. 2014. Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL-10 production. Nat. Commun. 5:3479
    [Google Scholar]
89. 89. 

    Hirschey MD, Zhao Y. 2015. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell Proteom. 14:2308–15
    [Google Scholar]
90. 90. 

    Du Y, Cai T, Li T, Xue P, Zhou B et al. 2015. Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins. Mol. Cell Proteom. 14:227–36
    [Google Scholar]
91. 91. 

    Galván-Peña S, Carroll RG, Newman C, Hinchy EC, Palsson-McDermott E et al. 2019. Malonylation of GAPDH is an inflammatory signal in macrophages. Nat. Commun. 10:338
    [Google Scholar]
92. 92. 

    Millet P, Vachharajani V, McPhail L, Yoza B, McCall CE 2016. GAPDH binding to TNF-α mRNA contributes to posttranscriptional repression in monocytes: a novel mechanism of communication between inflammation and metabolism. J. Immunol. 196:2541–51
    [Google Scholar]
93. 93. 

    Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC et al. 2011. Itaconic acid is a mammalian metabolite induced during macrophage activation. J. Am. Chem. Soc. 133:16386–89
    [Google Scholar]
94. 94. 

    Shin JH, Yang JY, Jeon BY, Yoon YJ, Cho SN et al. 2011. ¹H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J. Proteome Res 10:2238–47
    [Google Scholar]
95. 95. 

    McFadden BA, Purohit S. 1977. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. J. Bacteriol 131:136–44
    [Google Scholar]
96. 96. 

    Sasikaran J, Ziemski M, Zadora PK, Fleig A, Berg IA 2014. Bacterial itaconate degradation promotes pathogenicity. Nat. Chem. Biol. 10:371–77
    [Google Scholar]
97. 97. 

    Naujoks J, Tabeling C, Dill BD, Hoffmann C, Brown AS et al. 2016. IFNs modify the proteome of Legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLOS Pathog 12:e1005408
    [Google Scholar]
98. 98. 

    Nair S, Huynh JP, Lampropoulou V, Loginicheva E, Esaulova E et al. 2018. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J. Exp. Med. 215:1035–45
    [Google Scholar]
99. 99. 

    Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D et al. 2018. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556:113–17
    [Google Scholar]
100. 100. 

     Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E et al. 2018. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature 556:501–4
     [Google Scholar]
101. 101. 

     Ackermann WW, Potter VR. 1949. Enzyme inhibition in relation to chemotherapy. Proc. Soc. Exp. Biol. Med. 72:1–9
     [Google Scholar]
102. 102. 

     Qin W, Qin K, Zhang Y, Jia W, Chen Y et al. 2019. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol. 15:10983–91
     [Google Scholar]
103. 103. 

     Shen H, Campanello GC, Flicker D, Grabarek Z, Hu J et al. 2017. The human knockout gene CLYBL connects itaconate to vitamin B₁₂. Cell 171:771–82.e11
     [Google Scholar]
104. 104. 

     Nemeth B, Doczi J, Csete D, Kacso G, Ravasz D et al. 2016. Abolition of mitochondrial substrate-level phosphorylation by itaconic acid produced by LPS-induced Irg1 expression in cells of murine macrophage lineage. FASEB J 30:286–300
     [Google Scholar]
105. 105. 

     Daniels BP, Kofman SB, Smith JR, Norris GT, Snyder AG et al. 2019. The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to promote an antiviral metabolic state in neurons. Immunity 50:64–76.e4
     [Google Scholar]
106. 106. 

     Jang C, Hui S, Zeng X, Cowan AJ, Wang L et al. 2019. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab 30:594–606.e3
     [Google Scholar]
107. 107. 

     Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E et al. 2016. Metabolic heterogeneity in human lung tumors. Cell 164:681–94
     [Google Scholar]
108. 108. 

     Chen WW, Freinkman E, Wang T, Birsoy K, Sabatini DM 2016. Absolute quantification of matrix metabolites reveals the dynamics of mitochondrial metabolism. Cell 166:1324–37.e11
     [Google Scholar]
109. 109. 

     Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM et al. 2018. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360:449–53
     [Google Scholar]
110. 110. 

     Ooi M, Nishiumi S, Yoshie T, Shiomi Y, Kohashi M et al. 2011. GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis. Inflamm. Res. 60:831–40
     [Google Scholar]