Skip to main content

Advertisement

SpringerLink
Log in

Tricarboxylic acid cycle metabolites: new players in macrophage

  • Review
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Metabolic remodeling is a key feature of macrophage activation and polarization. Recent studies have demonstrated the role of tricarboxylic acid (TCA) cycle metabolites in the innate immune system. In the current review, we summarize recent advances in the metabolic reprogramming of the TCA cycle during macrophage activation and polarization and address the effects of these metabolites in modulating macrophage function. Deciphering the crosstalk between the TCA cycle and the immune response might provide novel potential targets for the intervention of immune reactions and favor the development of new strategies for the treatment of infection, inflammation, and cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

All data will be made available by the corresponding author upon reasonable request.

References

  1. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol. 2020;15:123–47.

    Article  CAS  PubMed  Google Scholar 

  2. Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541–66.

    Article  CAS  PubMed  Google Scholar 

  3. O’Neill LAJ, Artyomov MN. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol. 2019;19:273–81.

    Article  CAS  PubMed  Google Scholar 

  4. Wang F, Zhang S, Vuckovic I, Jeon R, Lerman A, Folmes CD, et al. Glycolytic stimulation is not a requirement for M2 macrophage differentiation. Cell Metab. 2018;28(463–475):e464.

    Google Scholar 

  5. Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25:771–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell. 2016;167(457–470):e413.

    Google Scholar 

  7. O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016;213:15–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jafri MS, Dudycha SJ, O’Rourke B. Cardiac energy metabolism: models of cellular respiration. Annu Rev Biomed Eng. 2001;3:57–81.

    Article  CAS  PubMed  Google Scholar 

  9. Feng X, Zhang L, Xu S, Shen AZ. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog Lipid Res. 2019;77:101006.

    Article  PubMed  Google Scholar 

  10. Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61:667–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Khanna S, Briggs Z, Rink C. Inducible glutamate oxaloacetate transaminase as a therapeutic target against ischemic stroke. Antioxid Redox Signal. 2015;22:175–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell. 2014;56:205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Mates JM, et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci U S A. 2011;108:8674–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ryan DG, O’Neill LAJ. Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett. 2017;591:2992–3006.

    Article  CAS  PubMed  Google Scholar 

  15. Noe JT, Mitchell RA. Tricarboxylic acid cycle metabolites in the control of macrophage activation and effector phenotypes. J Leukoc Biol. 2019;106:359–67.

    Article  CAS  PubMed  Google Scholar 

  16. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42:419–30.

    Article  CAS  PubMed  Google Scholar 

  17. De Souza DP, Achuthan A, Lee MK, Binger KJ, Lee MC, Davidson S, et al. Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages. J Clin Invest. 2019;129:4239–44.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18:985–94.

    Article  CAS  PubMed  Google Scholar 

  19. Fleetwood AJ, Dinh H, Cook AD, Hertzog PJ, Hamilton JA. GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol. 2009;86:411–21.

    Article  CAS  PubMed  Google Scholar 

  20. Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA, Calvello R, et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem J. 2011;438:433–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bishton MJ, Johnstone RW, Dickinson M, Harrison S, Prince HM. Overview of histone deacetylase inhibitors in haematological malignancies. Pharmaceuticals (Basel). 2010;3:2674–88.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  24. Luo Y, Wang Y, Shu Y, Lu Q, Xiao R. Epigenetic mechanisms: an emerging role in pathogenesis and its therapeutic potential in systemic sclerosis. Int J Biochem Cell Biol. 2015;67:92–100.

    Article  CAS  PubMed  Google Scholar 

  25. Lauterbach MA, Hanke JE, Serefidou M, Mangan MSJ, Kolbe CC, Hess T, et al. Toll-like receptor signaling rewires macrophage metabolism and promotes histone acetylation via ATP-citrate lyase. Immunity. 2019;51(997–1011):e1017.

    Google Scholar 

  26. Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci. 2005;62:1784–803.

    Article  CAS  PubMed  Google Scholar 

  27. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011;10(M111):012658.

    Google Scholar 

  28. Galvan-Pena S, Carroll RG, Newman C, Hinchy EC, Palsson-McDermott E, Robinson EK, et al. Malonylation of GAPDH is an inflammatory signal in macrophages. Nat Commun. 2019;10:338.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Infantino V, Pierri CL, Iacobazzi V. Metabolic routes in inflammation: the citrate pathway and its potential as therapeutic target. Curr Med Chem. 2018;26:7104–16.

    Article  Google Scholar 

  30. Zaslona Z, Palsson-McDermott EM, Menon D, Haneklaus M, Flis E, Prendeville H, et al. The induction of Pro-IL-1beta by lipopolysaccharide requires endogenous prostaglandin E2 production. J Immunol. 2017;198:3558–64.

    Article  CAS  PubMed  Google Scholar 

  31. Samuchiwal SK, Balestrieri B, Raff H, Boyce JA. Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. J Biol Chem. 2017;292:8195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marquez S, Fernandez JJ, Mancebo C, Herrero-Sanchez C, Alonso S, Sandoval TA, et al. Tricarboxylic acid cycle activity and remodeling of glycerophosphocholine lipids support cytokine induction in response to fungal patterns. Cell Rep. 2019;27(525–536):e524.

    Google Scholar 

  33. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014;15:323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim SK, Oh E, Yun M, Lee SB, Chae GT. Palmitate induces cisternal ER expansion via the activation of XBP-1/CCTalpha-mediated phospholipid accumulation in RAW 2647 cells. Lipids Health Dis. 2015;14:73.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC, Rabinowitz JD, et al. Itaconic acid is a mammalian metabolite induced during macrophage activation. J Am Chem Soc. 2011;133:16386–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A. 2013;110:7820–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 2016;24:158–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Baird L, Yamamoto M. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol. 2020. https://doi.org/10.1128/MCB.00099-20.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu M, Chen Y, Wang S, Zhou H, Feng D, Wei J, et al. Alpha-ketoglutarate modulates macrophage polarization through regulation of PPARgamma transcription and mTORC1/p70S6K pathway to ameliorate ALI/ARDS. Shock. 2020;53:103–13.

    Article  CAS  PubMed  Google Scholar 

  41. Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun. 2013;4:2834.

    Article  PubMed  Google Scholar 

  42. Di Conza G, Tsai CH, Ho PC. Fifty shades of alpha-ketoglutarate on cellular programming. Mol Cell. 2019;76:1–3.

    Article  PubMed  Google Scholar 

  43. TeSlaa T, Chaikovsky AC, Lipchina I, Escobar SL, Hochedlinger K, Huang J, et al. Alpha-ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 2016;24:485–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510:397–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013;496:238–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ma Y, Qi Y, Wang L, Zheng Z, Zhang Y, Zheng J. SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis. Free Radic Biol Med. 2019;134:458–67.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Keiran N, Ceperuelo-Mallafre V, Calvo E, Hernandez-Alvarez MI, Ejarque M, Nunez-Roa C, et al. SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity. Nat Immunol. 2019;20:581–92.

    Article  CAS  PubMed  Google Scholar 

  49. Macias-Ceja DC, Ortiz-Masia D, Salvador P, Gisbert-Ferrandiz L, Hernandez C, Hausmann M, et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 2019;12:178–87.

    Article  CAS  PubMed  Google Scholar 

  50. van Diepen JA, Robben JH, Hooiveld GJ, Carmone C, Alsady M, Boutens L, et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia. 2017;60:1304–13.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Peruzzotti-Jametti L, Bernstock JD, Vicario N, Costa ASH, Kwok CK, Leonardi T, et al. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell. 2018;22(355–368):e313.

    Google Scholar 

  52. Ghoreschi K, Bruck J, Kellerer C, Deng C, Peng H, Rothfuss O, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011;208:2291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Moharregh-Khiabani D, Linker RA, Gold R, Stangel M. Fumaric Acid and its esters: an emerging treatment for multiple sclerosis. Curr Neuropharmacol. 2009;7:60–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gold R, Linker RA, Stangel M. Fumaric acid and its esters: an emerging treatment for multiple sclerosis with antioxidative mechanism of action. Clin Immunol. 2012;142:44–8.

    Article  CAS  PubMed  Google Scholar 

  55. Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 2016;24:807–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Burgener AV, Bantug GR, Meyer BJ, Higgins R, Ghosh A, Bignucolo O, et al. SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2. Nat Immunol. 2019;20:1311–21.

    Article  CAS  PubMed  Google Scholar 

  57. Sanin DE, Matsushita M, Klein Geltink RI, Grzes KM, van Teijlingen BN, Corrado M, et al. Mitochondrial membrane potential regulates nuclear gene expression in macrophages exposed to prostaglandin E2. Immunity. 2018;49(1021–1033):e1026.

    Google Scholar 

  58. Ying W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008;10:179–206.

    Article  CAS  PubMed  Google Scholar 

  59. Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell. 2016;61:199–209.

    Article  CAS  PubMed  Google Scholar 

  60. Minhas PS, Liu L, Moon PK, Joshi AU, Dove C, Mhatre S, et al. Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation. Nat Immunol. 2019;20:50–63.

    Article  CAS  PubMed  Google Scholar 

  61. Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015;350:1208–13.

    Article  CAS  PubMed  Google Scholar 

  62. Kurundkar D, Kurundkar AR, Bone NB, Becker EJ Jr, Liu W, Chacko B, et al. SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury. JCI Insight. 2019. https://doi.org/10.1172/jci.insight.120722.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chen H, Wang C, Wei X, Ding X, Ying W. Malate-Aspartate shuttle inhibitor aminooxyacetate acid induces apoptosis and impairs energy metabolism of both resting microglia and LPS-activated microglia. Neurochem Res. 2015;40:1311–8.

    Article  CAS  PubMed  Google Scholar 

  64. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188–93.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by the National Natural Science Foundation of China (82104609).

Funding

National Natural Science Foundation of China, 82104609.

Author information

Author notes

  1. Ying Yang, Bing-Bing Cui contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Ying Yang, Bing-Bing Cui, Jian Li, Jiao-Jiao Shan, Jun Xu, Cheng-Yong Zhang & Ri-Ran Zhu

  2. Department of Traditional Chinese Medicine, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Xiao-Tong Wei

  3. Department of Hematology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Jing-Yi Wang

  4. Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China

    Jing-Yi Wang

  5. Key Laboratory of Integrated Traditional Chinese and Western Medicine for Hematology, Health Commission of Shandong Province, Jinan, 250014, China

    Jing-Yi Wang

Authors
  1. Ying Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bing-Bing Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiao-Jiao Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng-Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Tong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ri-Ran Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing-Yi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.Y. and C. B. B. wrote the manuscript and drew the picture. L. J., S. J. J., X. J., Z. C. Y., and W. X. T. drew the picture and edited the manuscript. Z. R. R. and W. J. Y. supervised the work and edited the manuscript. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Ri-Ran Zhu or Jing-Yi Wang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Cui, BB., Li, J. et al. Tricarboxylic acid cycle metabolites: new players in macrophage. Inflamm. Res. 73, 531–539 (2024). https://doi.org/10.1007/s00011-024-01853-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-024-01853-0

Keywords

Search

Navigation