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Itaconate: the poster child of metabolic reprogramming in macrophage function

Nature Reviews Immunology volume 19, pages 273–281 (2019)Cite this article

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Abstract

Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.

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Fig. 1: Metabolic remodelling of activating macrophages.
Fig. 2: Itaconate and chemical mimetics.
Fig. 3: Itaconate modifies proteins to elicit an anti-inflammatory effect.
Fig. 4: The intersection between itaconate and type I interferons.
Fig. 5: Itaconate, M2 macrophages, tumour-associated macrophages and immune-paralysed monocytes.

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References

  1. O’Neill, L. A. & Pearce, E. J. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213, 15–23 (2016).

    Article  Google Scholar 

  2. Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18, 488–498 (2017).

    Article  CAS  Google Scholar 

  3. Shin, J. H. et al. (1)H NMR-based metabolomic profiling in mice infected with Mycobacterium tuberculosis. J. Proteome Res. 10, 2238–2247 (2011).

    Article  CAS  Google Scholar 

  4. Strelko, C. L. et al. Itaconic acid is a mammalian metabolite induced during macrophage activation. J. Am. Chem. Soc. 133, 16386–16389 (2011).

    Article  CAS  Google Scholar 

  5. Sugimoto, M. et al. Non-targeted metabolite profiling in activated macrophage secretion. Metabolomics 8, 624–633 (2012). References 3–5 first reported that itaconate is produced by activated macrophages.

    Article  CAS  Google Scholar 

  6. Michelucci, A. et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc. Natl Acad. Sci. USA 110, 7820–7825 (2013). This study is the first identification of IRG1 as an enzyme that produces itaconate in activated macrophages.

    Article  CAS  Google Scholar 

  7. Nguyen, T. V., Alfaro, A. C., Merien, F., Young, T. & Grandiosa, R. Metabolic and immunological responses of male and female new Zealand Greenshell mussels (Perna canaliculus) infected with Vibrio sp. J. Invertebr. Pathol. 157, 80–89 (2018).

    Article  CAS  Google Scholar 

  8. Baup, S. Ueber eine neue Pyrogen-Citronensäure, und über Benennung der Pyrogen-Säuren überhaupt. Ann. Pharm. 19, 29–38 (1836).

    Article  Google Scholar 

  9. Crasso, G. L. Untersuchungen über das Verhalten der Citronsäure in höherer Temperatur und die daraus hervorgehenden Produkte. Justus Liebigs Ann. Chem. 34, 53–84 (1840).

    Article  Google Scholar 

  10. Turner, E. Elements of Chemistry: Including the Recent Discoveries and Doctrines of the Science (Cowperthwait & Co, 1840).

  11. Holmes, F. L. Hans Krebs: Architect of Intermediary Metabolism, 1933–1937 Vol. 2 (Oxford Univ. Press, 1993).

  12. Lee, C. G., Jenkins, N. A., Gilbert, D. J., Copeland, N. G. & O’Brien, W. E. Cloning and analysis of gene regulation of a novel LPS-inducible cDNA. Immunogenetics 41, 263–270 (1995).

    Article  CAS  Google Scholar 

  13. Kawai, T. & Akira, S. Toll-like receptor downstream signaling. Arthritis Res. Ther. 7, 12–19 (2005).

    Article  CAS  Google Scholar 

  14. Basagoudanavar, S. H. et al. Distinct roles for the NF-kappa B RelA subunit during antiviral innate immune responses. J. Virol. 85, 2599–2610 (2011).

    Article  CAS  Google Scholar 

  15. Rao, G. R. & McFadden, B. A. Isocitrate lyase from Pseudomonas indigofera. IV. Specificity and inhibition. Arch. Biochem. Biophys. 112, 294–303 (1965).

    Article  CAS  Google Scholar 

  16. Williams, J. O., Roche, T. E. & McFadden, B. A. Mechanism of action of isocitrate lyase from Pseudomonas indigofera. Biochemistry 10, 1384–1390 (1971).

    Article  CAS  Google Scholar 

  17. Rittenhouse, J. W. & McFadden, B. A. Inhibition of isocitrate lyase from Pseudomonas indigofera by itaconate. Arch. Biochem. Biophys. 163, 79–86 (1974).

    Article  CAS  Google Scholar 

  18. McFadden, B. A. & Purohit, S. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. J. Bacteriol. 131, 136–144 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Berg, I. A., Filatova, L. V. & Ivanovsky, R. N. Inhibition of acetate and propionate assimilation by itaconate via propionyl-CoA carboxylase in isocitrate lyase-negative purple bacterium Rhodospirillum rubrum. FEMS Microbiol. Lett. 216, 49–54 (2002).

    Article  CAS  Google Scholar 

  20. Naujoks, J. et al. IFNs modify the proteome of Legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLOS Pathog. 12, e1005408 (2016).

    Article  Google Scholar 

  21. Hammerer, F., Chang, J. H., Duncan, D., Castaneda Ruiz, A. & Auclair, K. Small molecule restores itaconate sensitivity in Salmonella enterica: a potential new approach to treating bacterial infections. ChemBioChem 17, 1513–1517 (2016).

    Article  CAS  Google Scholar 

  22. Sasikaran, J., Ziemski, M., Zadora, P. K., Fleig, A. & Berg, I. A. Bacterial itaconate degradation promotes pathogenicity. Nat. Chem. Biol. 10, 371–377 (2014).

    Article  CAS  Google Scholar 

  23. Kinoshita, K. Uber eine neue Aspergillus Art, A. itaconicus. Bot. Mag. Tokyo 45, 45–50 (1931).

    Article  Google Scholar 

  24. Calam, C. T., Oxford, A. E. & Raistrick, H. Studies in the biochemistry of micro-organisms: itaconic acid, a metabolic product of a strain of Aspergillus terreus Thom. Biochem. J. 33, 1488–1495 (1939).

    Article  CAS  Google Scholar 

  25. Bonnarme, P. et al. Itaconate biosynthesis in Aspergillus terreus. J. Bacteriol. 177, 3573–3578 (1995).

    Article  CAS  Google Scholar 

  26. Kim, J. et al. Production of itaconate by whole-cell bioconversion of citrate mediated by expression of multiple cis-aconitate decarboxylase (cadA) genes in Escherichia coli. Sci. Rep. 7, 39768 (2017).

    Article  CAS  Google Scholar 

  27. Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016). This paper presents the first identification of itaconate as an immunoregulatory anti-inflammatory metabolite that inhibits SDH in macrophages.

    Article  CAS  Google Scholar 

  28. Chen, B., Zhang, D. & Pollard, J. W. Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) in the uterine epithelium during implantation through the protein kinase C pathway. Mol. Endocrinol. 17, 2340–2354 (2003).

    Article  CAS  Google Scholar 

  29. Cheon, Y. P., Xu, X., Bagchi, M. K. & Bagchi, I. C. Immune-responsive gene 1 is a novel target of progesterone receptor and plays a critical role during implantation in the mouse. Endocrinology 144, 5623–5630 (2003).

    Article  CAS  Google Scholar 

  30. Nair, S. et al. Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection. J. Exp. Med. 215, 1035–1045 (2018). This study is the first to report a major infection phenotype of IRG1-deficient mice, comprising poor survival following M. tuberculosis infection.

    Article  CAS  Google Scholar 

  31. Degrandi, D., Hoffmann, R., Beuter-Gunia, C. & Pfeffer, K. The proinflammatory cytokine-induced IRG1 protein associates with mitochondria. J. Interferon Cytokine Res. 29, 55–67 (2009).

    Article  CAS  Google Scholar 

  32. Krawczyk, C. M. et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115, 4742–4749 (2010).

    Article  CAS  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013).

    Article  CAS  Google Scholar 

  35. Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).

    Article  CAS  Google Scholar 

  36. Ackermann, W. W. & Potter, V. R. Enzyme inhibition in relation to chemotherapy. Proc. Soc. Exp. Biol. Med. 72, 1–9 (1949).

    Article  CAS  Google Scholar 

  37. Dervartanian, D. V. & Veeger, C. Studies on succinate dehydrogenase. I. Spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes. Biochim. Biophys. Acta 92, 233–247 (1964).

    CAS  PubMed  Google Scholar 

  38. Dervartanian, D. V. & Veeger, C. Studies on succinate dehydrogenase. II. On the nature of the reaction of competitive inhibitors and substrates with succinate dehydrogenase. Biochim. Biophys. Acta 105, 424–436 (1965).

    Article  CAS  Google Scholar 

  39. Sakai, A., Kusumoto, A., Kiso, Y. & Furuya, E. Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver. Nutrition 20, 997–1002 (2004).

    Article  CAS  Google Scholar 

  40. Nemeth, B. et al. 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 (2016).

    Article  CAS  Google Scholar 

  41. Booth, A. N., Taylor, J., Wilson, R. H. & Deeds, F. The inhibitory effects of itaconic acid in vitro and in vivo. J. Biol. Chem. 195, 697–702 (1952).

    CAS  PubMed  Google Scholar 

  42. Adler, J., Wang, S. F. & Lardy, H. A. The metabolism of itaconic acid by liver mitochondria. J. Biol. Chem. 229, 865–879 (1957).

    CAS  PubMed  Google Scholar 

  43. Wang, S. F., Adler, J. & Lardy, H. A. The pathway of itaconate metabolism by liver mitochondria. J. Biol. Chem. 236, 26–30 (1961).

    CAS  PubMed  Google Scholar 

  44. Pajor, A. M. Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family. Pflügers Arch. 466, 119–130 (2014).

    Article  CAS  Google Scholar 

  45. Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470 (2016).

    Article  CAS  Google Scholar 

  46. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IkappaBzeta-ATF3 inflammatory axis. Nature 556, 501–504 (2018). This study is the first to report that endogenous itaconate is an electrophilic metabolite that triggers NRF2 and ATF3 and binds to glutathione.

    Article  CAS  Google Scholar 

  47. Ahmed, S. M., Luo, L., Namani, A., Wang, X. J. & Tang, X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 585–597 (2017).

    Article  CAS  Google Scholar 

  48. Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199–218 (2014).

    Article  CAS  Google Scholar 

  49. Kobayashi, E. H. et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7, 11624 (2016).

    Article  CAS  Google Scholar 

  50. Linker, R. A. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134, 678–692 (2011).

    Article  Google Scholar 

  51. Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).

    Article  CAS  Google Scholar 

  52. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    Article  CAS  Google Scholar 

  53. Levonen, A. L., Hill, B. G., Kansanen, E., Zhang, J. & Darley-Usmar, V. M. Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics. Free Radic. Biol. Med. 71, 196–207 (2014).

    Article  CAS  Google Scholar 

  54. Gilchrist, M. et al. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441, 173–178 (2006).

    Article  CAS  Google Scholar 

  55. Quiros, P. M., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 17, 213–226 (2016).

    Article  CAS  Google Scholar 

  56. Tsoi, L. C. et al. Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci. Nat. Commun. 6, 7001 (2015).

    Article  CAS  Google Scholar 

  57. Chapman, S. J. et al. NFKBIZ polymorphisms and susceptibility to pneumococcal disease in European and African populations. Genes Immun. 11, 319–325 (2010).

    Article  CAS  Google Scholar 

  58. ElAzzouny, M. et al. Dimethyl itaconate is not metabolized into itaconate intracellularly. J. Biol. Chem. 292, 4766–4769 (2017).

    Article  CAS  Google Scholar 

  59. Shen, H. et al. The human knockout gene CLYBL connects itaconate to vitamin B12. Cell 171, 771–782 (2017).

    Article  CAS  Google Scholar 

  60. Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).

    Article  Google Scholar 

  61. Labzin, L. I. et al. ATF3 is a key regulator of macrophage IFN responses. J. Immunol. 195, 4446–4455 (2015).

    Article  CAS  Google Scholar 

  62. Nelson, V. L. et al. PPARgamma is a nexus controlling alternative activation of macrophages via glutamine metabolism. Genes Dev. 32, 1035–1044 (2018).

    Article  CAS  Google Scholar 

  63. Ganta, V. C. et al. A microRNA93-interferon regulatory factor-9-immunoresponsive gene-1-itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle. Circulation 135, 2403–2425 (2017).

    Article  CAS  Google Scholar 

  64. Weiss, J. M. et al. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Invest. 128, 3794–3805 (2018).

    Article  Google Scholar 

  65. Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013).

    Article  CAS  Google Scholar 

  66. Hall, C. J. et al. Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab. 18, 265–278 (2013).

    Article  CAS  Google Scholar 

  67. Dominguez-Andres, J. et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 29, 211–220 (2018).

    Article  Google Scholar 

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Acknowledgements

M.N.A. thanks his colleagues in the Department of Pathology and Immunology at the Washington University School of Medicine for guidance and advice.

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Nature Reviews Immunology thanks K. Hiller, T. Horng and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Luke A. J. O’Neill

  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    Maxim N. Artyomov

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L.A.J.O. and M.N.A. both wrote and edited the manuscript.

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Glossary

Glycolysis

A metabolic pathway that generates the cellular high-energy store of ATP by oxidizing glucose to pyruvate. In eukaryotic cells, pyruvate is further oxidized in mitochondria into CO2 and H2O via the tricarboxylic acid cycle in a process known as ‘aerobic respiration’. This results in a net yield of 36–38 molecules of ATP per metabolized molecule of glucose.

Tricarboxylic acid cycle

(TCA cycle; also known as the Krebs cycle or citric acid cycle). This pathway catalyses the oxidation of acetyl-CoA (from glucose or fatty acids, or indirectly from amino acids) to generate NADH and FADH, which fuel the electron transport chain and thereby oxidative phosphorylation and ATP production. The TCA cycle also serves as a source of precursors for amino acid and lipid synthesis.

Anaplerotic cycle

A ‘broken’ metabolic cycle, occurring when there is no further continuous metabolic flux across the cycle and individual reactions are rendered inactive or incorporated into different pathways.

Hypoxia-inducible factor 1α

(HIF1α). A transcription factor that regulates the expression of many metabolic enzymes (especially in the glycolysis pathway) and inflammatory mediators such as IL-1β.

Reverse electron transport

A state of the electron transport chain when electrons are flowing in the opposite direction.

Oxidative stress

Cells continuously produce reactive oxygen species (ROS) such as hydrogen peroxide or superoxide anions. Under physiological conditions, mitochondria are the main source, and cellular antioxidants ensure that the redox equilibrium is maintained. During inflammatory responses, major cytosolic production of ROS and reactive nitric oxide species also contributes to creating oxidative stress.

Electrophilic stress response

(ESR). A cellular response to endogenous and exogenous metabolites and compounds that can serve as electrophiles (that is, compounds capable of accepting an electron pair (Michael acceptors)). Electrophiles are highly reactive to sulfhydryl groups in the cell.

M2 macrophages

‘M1’ and ‘M2’ are somewhat artificial classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with IFNγ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regards to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

Oxidative phosphorylation

The metabolic pathway that occurs at the inner mitochondrial membrane and uses an electrochemical gradient created by the oxidation of electron carriers to generate ATP.

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O’Neill, L.A.J., Artyomov, M.N. Itaconate: the poster child of metabolic reprogramming in macrophage function. Nat Rev Immunol 19, 273–281 (2019). https://doi.org/10.1038/s41577-019-0128-5

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