Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense
Open accessAbstract
Itaconate is a newly discovered mammalian metabolite bearing significant implications for our understanding of cellular immunometabolism and antimicrobial defense. Here, we explore recent findings regarding the role of itaconate in the innate immune response and highlight the emerging principle that metabolites can have distinct immunological functions independent of bioenergetics.
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“However, such an immunosuppressive role is inconsistent with data from zebrafish macrophage-lineage cells showing that Irg1/Acod1 is necessary to generate ROS from fatty acid oxidation (Hall et al., 2013).”
BackgroundEnzyme Inhibition in Relation to Chemotherapy.
Ackermann, W. W., & Potter, V. R. (1949) · Experimental Biology and Medicine · doi:10.3181/00379727-72-17313 · Cited by 262 · cited 1× · see citing works
“It was demonstrated over 60 years ago that itaconate can competitively inhibit succinate dehydrogenase (SDH) function (Ackermann and Potter, 1949).”
Naujoks, J., Tabeling, C., Dill, B. D., Hoffmann, C., Brown, A. S., Kunze, M., Kempa, S., Peter, A., Mollenkopf, H.-J., Dorhoi, A., et al. (2016) · PLOS Pathogens · doi:10.1371/journal.ppat.1005408 · Cited by 261 · see citing works
25-Hydroxycholesterol acts as an amplifier of inflammatory signaling
Gold, E. S., Diercks, A. H., Podolsky, I., Podyminogin, R. L., Askovich, P. S., Treuting, P. M., & Aderem, A. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404271111 · Cited by 250 · see citing works
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“Then in 2011, three groups described mammalian itaconate production in three separate immune-related contexts: in the lungs of Mycobacterium tuberculosis (MTB)-infectedmice (Shin et al., 2011), in the supernatant of LPS-treated macrophage-like RAW264.”
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Medium-chain Fatty Acid-sensing Receptor, GPR84, Is a Proinflammatory Receptor
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Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera
McFadden, B. A., & Purohit, S. (1977) · Journal of Bacteriology · doi:10.1128/jb.131.1.136-144.1977 · Cited by 220 · cited 3× · see citing works
“indigofera is sufficient to dramatically inhibit bacterial growth, thereby suggesting that itaconate inhibits bacterial growth in glucose-poor conditions (McFadden and Purohit, 1977).”
BackgroundInfluentialBiochemistry of microbial itaconic acid production
Steiger, M. G., Blumhoff, M. L., Mattanovich, D., & Sauer, M. (2013) · Frontiers in Microbiology · doi:10.3389/fmicb.2013.00023 · Cited by 185 · cited 1× · see citing works
“Research into more efficient methods of biomanufacturing itaconate is extremely active because it represents a sustainable alternative to traditional crude-oil-based polymers (Steiger et al., 2013).”
BackgroundItaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite
Cordes, T., Michelucci, A., & Hiller, K. (2015) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071714-034243 · Cited by 183 · cited 7× · see citing works
“In 1931, it was reported that itaconate could be synthesized in vivo by an Aspergillus species (subsequently named Aspergillus itaconcus) isolated from dried salted plums.”
BackgroundInfluentialCloning and analysis of gene regulation of a novel LPS-inducible cDNA
Lee, C. L., Jenkins, N., Gilbert, D., Copeland, N., & O'Brien, W. (1995) · Immunogenetics · doi:10.1007/bf00172150 · Cited by 165 · cited 2× · see citing works
“cloned immunoresponsive gene 1 (Irg1), which they found to be highly upregulated upon treatment of murine peritoneal macrophages with lipopolysaccharide (LPS) (Lee et al., 1995).”
BackgroundKorf, H., Beken, S. V., Romano, M., Steffensen, K. R., Stijlemans, B., Gustafsson, J.-�., Grooten, J., & Huygen, K. (2009) · Journal of Clinical Investigation · doi:10.1172/jci35288 · Cited by 164 · see citing works
The proinflammatory cytokine-induced IRG1 protein associates with mitochondria
Degrandi, D., Hoffmann, R., Beuter-Gunia, C., & Pfeffer, K. (2009) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2008.0013 · Cited by 155 · cited 1× · see citing works
“In the murine macrophage, IRG1/CAD is exclusively localized to mitochondria, which are of bacterial origin (Degrandi et al., 2009).”
BackgroundCoordinate regulation of neutrophil homeostasis by liver X receptors in mice
Hong, C., Kidani, Y., A-González, N., Phung, T., Ito, A., Rong, X., Ericson, K. R., Mikkola, H. K. A., Beaven, S. W., Miller, L. S., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci58393 · Cited by 152 · see citing works
Endophytic fungi—The treasure chest of antibacterial substances
Radić, N., & Štrukelj, B. (2012) · Phytomedicine · doi:10.1016/j.phymed.2012.09.007 · Cited by 134 · cited 1× · see citing works
“A number of endophytic fungi, which live symbiotically with plants, have also been reported to generate an array of antibacterial metabolites (Kaul et al., 2012; Radi c and Strukelj, 2012).”
BackgroundUddin, M. J., Joe, Y., Kim, S., Jeong, S. O., Ryter, S. W., Pae, H., & Chung, H. (2015) · Cellular and Molecular Immunology · doi:10.1038/cmi.2015.02 · Cited by 130 · cited 2× · see citing works
“Such an immunoregulatory model is supported by studies showing that Irg1/Acod1 is necessary for the immunosuppressive effects of HO-1 (Jamal Uddin et al., 2016) and that Irg1/Acod1 plays a critical role in embryo implantation, a process thought to require immunosuppression (Chen et al., 2003; Cheon…”
BackgroundResultThe role of HCA2 (GPR109A) in regulating macrophage function
Zandi‐Nejad, K., Takakura, A., Jurewicz, M. M., Chandraker, A. K., Offermanns, S., Mount, D. B., & Abdi, R. (2013) · The FASEB Journal · doi:10.1096/fj.12-223933 · Cited by 119 · cited 1× · see citing works
“…13, 2016 Activation of BHOB receptor GPR109A (also known as HCA2 or HCAR2) suppresses macrophage and monocyte response to LPS (Digby et al., 2012; Zandi-Nejad et al., 2013), inhibits progression of atherosclerosis (Lukasova et al., 2011), and inhibits lymphocyte infiltration in models of stroke…”
BackgroundVenkataraman, C., & Kuo, F. (2005) · Immunology Letters · doi:10.1016/j.imlet.2005.05.010 · Cited by 110 · see citing works
Mechanism of action of isocitrate lyase from Pseudomonas indigofera
McFadden, B. A., Williams, J. O., & Roche, T. E. (1971) · Biochemistry · doi:10.1021/bi00784a017 · Cited by 99 · cited 1× · see citing works
“It was first described in 1971 that itaconate effectively inhibits lyase (ICL) from the Gram-negative bacterium Vogesella indigofera (Williams et al., 1971).”
BackgroundNon-targeted metabolite profiling in activated macrophage secretion
Sugimoto, M., Sakagami, H., Yokote, Y., Onuma, H., Kaneko, M., Mori, M., Sakaguchi, Y., Soga, T., & Tomita, M. (2012) · Metabolomics · doi:10.1007/s11306-011-0353-9 · Cited by 95 · cited 2× · see citing works
“7 cells (Sugimoto et al., 2011), and in the intracellular compartment of glia-like VM-M3 cells (Strelko et al., 2011).”
BackgroundCheon, Y.-P., Xu, X., Bagchi, M. K., & Bagchi, I. C. (2003) · Endocrinology · doi:10.1210/en.2003-0585 · Cited by 76 · cited 1× · see citing works
“…by studies showing that Irg1/Acod1 is necessary for the immunosuppressive effects of HO-1 (Jamal Uddin et al., 2016) and that Irg1/Acod1 plays a critical role in embryo implantation, a process thought to require immunosuppression (Chen et al., 2003; Cheon et al., 2003; Sherwin et al., 2004).”
BackgroundRen, K., Lv, Y., Zhuo, Y., Chen, C., Shi, H., Guo, L., Yang, G., Hou, Y., Tan, R. X., & Li, E. (2016) · Journal of Virology · doi:10.1128/jvi.00563-16 · Cited by 73 · cited 1× · see citing works
“While the same has not been shown for itaconate, a recent study does report that viral infection of the lung adenocarcinoma cell line A549 can induce Irg1/Acod1 expression, suggesting that non-immune cells may also be able to generate itaconate (Ren et al., 2016).”
BackgroundSherwin, J. R. A., Freeman, T. C., Stephens, R. J., Kimber, S., Smith, A. G., Chambers, I., Smith, S. K., & Sharkey, A. M. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0110 · Cited by 68 · see citing works
Ueber eine neue Pyrogen‐Citronensäure, und über Benennung der Pyrogen‐Säuren überhaupt
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“…by studies showing that Irg1/Acod1 is necessary for the immunosuppressive effects of HO-1 (Jamal Uddin et al., 2016) and that Irg1/Acod1 plays a critical role in embryo implantation, a process thought to require immunosuppression (Chen et al., 2003; Cheon et al., 2003; Sherwin et al., 2004).”
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EBI2 Is a Negative Regulator of Type I Interferons in Plasmacytoid and Myeloid Dendritic Cells
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Elements of Chemistry, Including the Actual State and Prevalent Doctrines of the Science.
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Metabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 796 · see citing works
“Although itaconate plays a decisive inflammatory role in activated macrophages and modifies a variety of proteins on cysteine residues (Luan and Medzhitov, 2016; Murphy and O’Neill, 2018; Nonnenmacher and Hiller, 2018; O’Neill and Artyomov, 2019; Yu et al., 2019), it is not clear whether itaconate…”
BackgroundInfluentialGPCR-Mediated Signaling of Metabolites
Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A., & Schwartz, T. W. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.03.008 · Cited by 586 · see citing works
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“There is a discussion as to the relevance of these studies due to differences in concentrations of itaconate used both in terms of the variety of concentrations used exogenously to inhibit bacterial growth and the range in reported intracellular concentrations (101, 102).”
Background4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects
Liao, S., Han, C., Xu, D., Fu, X., Wang, J., & Kong, L. (2019) · Nature Communications · doi:10.1038/s41467-019-13078-5 · Cited by 457 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
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Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers
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Metabolism as a guiding force for immunity
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Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth
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Mitochondria reactive oxygen species signaling in immune responses
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The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12
Shen, H., Campanello, G. C., Flicker, D., Grabarek, Z., Hu, J., Luo, C., Banerjee, R. V., & Mootha, V. K. (2017) · Cell · doi:10.1016/j.cell.2017.09.051 · Cited by 152 · see citing works
“More recently, itaconate has been described as an anti-inflammatory metabolite whose activity is mediated, in part, by its ability to inhibit succinate dehydrogenase (SDH) and prevent reactive oxygen species (ROS) generation (Cordes et al., 2016; Lampropoulou et al., 2016; Luan and Medzhitov, 2016).”
Krebs cycle rewired for macrophage and dendritic cell effector functions
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The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response
Icard, P., Lincet, H., Wu, Z., Coquerel, A., Forgez, P., Alifano, M., & Fournel, L. (2020) · Biochimie · doi:10.1016/j.biochi.2020.11.010 · Cited by 140 · see citing works
“This molecule promotes activation of ATF3 (a negative regulator of cytokines production as IL-6) and of nuclear factor erythroid 2-related factor 2 (NRF2) inducing resolution of inflammation and repair [61,62] (Fig.”
Natural bio-based monomers for biomedical applications: a review
Birajdar, M. S., Joo, H., Koh, W., & Park, H. (2021) · Biomaterials Research · doi:10.1186/s40824-021-00208-8 · Cited by 135 · see citing works
TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages
Schuster, E.-M., Epple, M. W., Glaser, K. M., Mihlan, M., Lucht, K., Zimmermann, J. A., Bremser, A., Polyzou, A., Obier, N., Cabezas‐Wallscheid, N., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00605-w · Cited by 108 · see citing works
Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst
Tomlinson, K. L., Riquelme, S. A., Baskota, S. U., Drikic, M., Monk, I. R., Stinear, T. P., Lewis, I. A., & Prince, A. S. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112064 · Cited by 101 · see citing works
Innate Immune Memory and the Host Response to Infection
Sherwood, E. R., Burelbach, K. R., McBride, M. A., Stothers, C. L., Owen, A. M., Hernandez, A., Patil, N. K., Williams, D. L., & Bohannon, J. K. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2101058 · Cited by 95 · see citing works
Burch, J. S., Marcero, J. R., Maschek, J. A., Cox, J. E., Jackson, L. K., Medlock, A. E., Phillips, J. D., & Dailey, H. A. (2018) · Blood · doi:10.1182/blood-2018-01-829036 · Cited by 92 · see citing works
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Itaconate: an emerging determinant of inflammation in activated macrophages
Yu, X., Zhang, D., Zheng, X., & Tang, C. (2018) · Immunology and Cell Biology · doi:10.1111/imcb.12218 · Cited by 88 · see citing works
“Aconitase 2 catalyzes citrate, an intermediate metabolite of this cycle, to form cis-aconitate that is decarboxylated by cis-aconitate decarboxylase leading to itaconate production (Figure 1a).(9) This represents the first metabolic breakpoint in the TCA cycle since the inhibition of isocitrate dehydrogenase that cata…”
BackgroundWang, H., Fedorov, A. A., Fedorov, E. V., Hunt, D. M., Rodgers, A., Douglas, H. L., Garza-Garcı́a, A., Bonanno, J. B., Almo, S. C., & de Carvalho, L. P. S. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906606116 · Cited by 76 · see citing works
“In contrast to the established antimicrobial character of this molecule, itaconate is present in some prokaryotes (12, 14 – 17, 20, 21, 23, 43, 44).”
Peruzzotti‐Jametti, L., & Pluchino, S. (2018) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.07.007 · Cited by 72 · see citing works
“Extracellular metabolites can also act as key signalling molecules, both at the organismal level and within specific inflammatory microenvironments [61].”
BackgroundDimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO‐1 signaling pathway
Gu, L., Lin, J., Wang, Q., Cui, L., Peng, X., Fan, Y., Lu, C., Lin, H., Niu, Y., Zhu, G., et al. (2020) · Immunology and Cell Biology · doi:10.1111/imcb.12316 · Cited by 74 · see citing works
“The glyoxylate shunt is absent in animals but determines the survival and growth of pathogens in low-glucose environments.(30) A growing body of evidence has highlighted the antimicrobial role of itaconate against pathogens during inflammation.”
BackgroundItaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase
Kwai, B. X. C., Collins, A. J., Middleditch, M., Sperry, J., Bashiri, G., & Leung, I. K. H. (2020) · RSC Medicinal Chemistry · doi:10.1039/d0md00301h · Cited by 70 · see citing works
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Metabolic reprogramming: an innate cellular defence mechanism against intracellular bacteria?
Escoll, P., & Buchrieser, C. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.05.009 · Cited by 61 · see citing works
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The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in lethal innate immunity
Chen, F., Wu, R., Liu, J., Kang, R., Li, J., & Tang, D. (2022) · iScience · doi:10.1016/j.isci.2022.104561 · Cited by 50 · see citing works
“Itaconate also inhibits the function of phagocytes to eliminate pathogens (Michelucci et al., 2013; Naujoks et al., 2016), indicating a dual role of the ACOD1-itaconate axis in infection (Luan and Medzhitov, 2016; Wu et al., 2020).”
BackgroundCrosstalk Between Staphylococcus aureus and Innate Immunity: Focus on Immunometabolism
Horn, C. M., & Kielian, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.621750 · Cited by 51 · see citing works
“Via this mechanism, itaconate represents a way to counterbalance the proinflammatory activity of succinate accumulation (65, 66).”
BackgroundDaly, R., Blackburn, G. J., Best, C., Goodyear, C. S., Mudaliar, M., Burgess, K. E., Stirling, A., Porter, D. R., McInnes, I. B., Barrett, M. P., et al. (2020) · Metabolites · doi:10.3390/metabo10060241 · Cited by 49 · see citing works
“In other studies, itaconate appears to be involved in the regulation of inflammation, its elevation leading, ultimately, to suppression of the inflammatory response [29] and although functional roles in human inflammatory disease have yet to be reported, our studies indicate levels are elevated as inflammation is dimi…”
BackgroundModulation of the Itaconate Pathway Attenuates Murine Lupus
Blanco, L. P., Patiño‐Martínez, E., Nakabo, S., Zhang, M., Pedersen, H. L., Wang, X., Carmona‐Rivera, C., Claybaugh, D., Yu, Z., Desta, E., et al. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42284 · Cited by 49 · see citing works
“oxidative stress–related responses (12).”
Dixit, A., Sabnis, A., Balgude, D., Kale, S., Gada, A. H., Kudu, B., Mehta, K., Kasar, S., Handa, D., Mehta, R., et al. (2023) · Polymer Bulletin · doi:10.1007/s00289-022-04638-9 · Cited by 47 · see citing works
Regulation of leukocyte function by citric acid cycle intermediates
Patil, N. K., Bohannon, J. K., Hernandez, A., Patil, T. K., & Sherwood, E. R. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mir1118-415r · Cited by 49 · see citing works
The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer
Wang, Q., Li, X. L., Mei, Y., Ye, J.-C., Fan, W., Cheng, G., Zeng, M., & Feng, G. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01963-2 · Cited by 46 · see citing works
Epithelial inflammasomes in the defense against Salmonella gut infection
Fattinger, S. A., Sellin, M. E., & Hardt, W. (2020) · Current Opinion in Microbiology · doi:10.1016/j.mib.2020.09.014 · Cited by 41 · see citing works
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Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection
Forde, A. J., Kolter, J., Zwicky, P., Baasch, S., Lohrmann, F., Eckert, M., Gres, V., Lagies, S., Gorka, O., Rambold, A. S., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.adg3517 · Cited by 33 · see citing works
Kim, G.-L., Hooven, T. A., Norambuena, J., Li, B., Boyd, J. M., Yang, J. H., & Parker, D. (2021) · mBio · doi:10.1128/mbio.00814-21 · Cited by 38 · see citing works
“The host metabolite itaconate influences biofilm formation in several other bacterial species (24) and has been shown to exhibit antimicrobial properties (25).”
BackgroundLai, R. P. J., Cortes, T., Marais, S., Rockwood, N., Burke, M. L., Garza-Garcı́a, A., Horswell, S. D., Sesay, A. K., O’Garra, A., Young, D. B., et al. (2021) · mBio · doi:10.1128/mbio.01766-21 · Cited by 36 · see citing works
Itaconic acid indicates cellular but not systemic immune system activation
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“However, absolute quantifications of IA are so far lacking and the potential effects of extracellular IA are unclear to date [9].”
BackgroundMolecular mechanisms and systemic targeting of NRF2 dysregulation in cancer
Kang, J.-S., Nam, L. B., Yoo, O.-K., & Keum, Y. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114002 · Cited by 34 · see citing works
Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity
Chen, C., Liu, C., Sun, P., Zhang, Z., Wang, Z., Liu, P., & Li, X. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.07.011 · Cited by 33 · see citing works
Ironing out Macrophage Immunometabolism
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“TLR4-mediated induction of cis-aconitic acid decarboxylase/immune-responsive gene 1 (CAD/Irg1), an enzyme that drives the conversion of cis-aconitate, the intermediate between citrate and isocitrate in the TCA cycle, to itaconate, a metabolite possessing both anti-inflammatory and anti-microbial properties [16] (Figur…”
BackgroundNew Avenues of Heme Synthesis Regulation
Medlock, A. E., & Dailey, H. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137467 · Cited by 33 · see citing works
Tran, T. L. C., Callahan, D. L., Islam, M. T., Wang, Y., Arioli, T., & Cahill, D. M. (2023) · Frontiers in Plant Science · doi:10.3389/fpls.2023.1114172 · Cited by 33 · see citing works
“It has been proposed that itaconic acid plays a role as an antimicrobial metabolite due to its inhibitory effect on isocitrate lyase, a key enzyme in the glyoxylate pathway (a variation of the TCA cycle), contributing to limiting the growth of various pathogens (Cordes et al., 2015; Luan and Medzhitov, 2016).”
BackgroundItaconate alleviates diet-induced obesity via activation of brown adipocyte thermogenesis
Yu, Z., Li, X., Quan, Y., Chen, J., Liu, J., Zheng, N., Liu, S., Wang, Y., Liu, W., Qiu, C., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114142 · Cited by 32 · see citing works
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Loss of CNFY toxin-induced inflammation drives Yersinia pseudotuberculosis into persistency
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The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages
Li, Y., Gong, W., Li, W., Liu, P., Liu, J., Jiang, H., Zheng, T., Wu, J., Wu, X., Zhao, Y., et al. (2022) · International Reviews of Immunology · doi:10.1080/08830185.2022.2067153 · Cited by 29 · see citing works
“Isocitrate lyase (ICL) is an important enzyme for glyoxylic acid shunting which is a survival strategy for bacteria and allows bacteria to utilize the carbon source produced from acety l-CoA under glucose-limited conditions [23,24,41].”
BackgroundEffect of pH on the antimicrobial activity of the macrophage metabolite itaconate
Duncan, D., Lupien, A., Behr, M. A., & Auclair, K. (2021) · Microbiology · doi:10.1099/mic.0.001050 · Cited by 27 · see citing works
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Elastomeric Polyesters in Cardiovascular Tissue Engineering and Organs-on-a-Chip
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Immunometabolic Regulation of Bacterial Infection, Biofilms, and Antibiotic Susceptibility
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“In addition to preserving tissue homeostasis by attenuating macrophage in fl ammation, itaconate also safeguards organ integrity by acting as a strong micro-bicidal agent [121, 122].”
BackgroundHong, N. E., Chaplin, A. M. L., Di, L., Ravodina, A. M., Bevan, G. H., Gao, H., Asase, C., Gangwar, R. S., Cameron, M. J., Mignery, M., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114911 · Cited by 20 · see citing works
Metabolic adaptations driving innate immune memory: mechanisms and therapeutic implications
Hao, D., McBride, M. A., Bohannon, J. K., Hernandez, A., Klein, B., Williams, D. L., & Sherwood, E. R. (2025) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiaf037 · Cited by 21 · see citing works
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“Recent studies have found that IRG1-induced ITA inhibits succinate dehydrogenase (SDH) expression and activity, thereby blocking succinate-mediated inflammatory responses [29] and preventing reverse electron transfer-generated reactive oxygen species to decrease inflammatory responses [30].”
BackgroundLiang, J., Na, X., Meng, L., He, L., Shu, T., Fang, Y., Zhang, B., Zhao, Z., Guo, C., Li, J., et al. (2025) · MedComm · doi:10.1002/mco2.70245 · Cited by 15 · see citing works
Roberts, L. M., Leighton, I. A., Schwarz, B. H., Wehrly, T. D., Evans, T. J., & Bosio, C. M. (2022) · Cellular Immunology · doi:10.1016/j.cellimm.2022.104485 · Cited by 16 · see citing works
Sputum Metabolites Associated with Nontuberculous Mycobacterial Infection in Cystic Fibrosis
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Investigating the Role of Metabolism for Antibiotic Combination Therapies in Pseudomonas aeruginosa
Golden, M. M., Post, S. J., Rivera, R., & Wuest, W. M. (2023) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.3c00452 · Cited by 13 · see citing works
“30 However, it was not selected because P. aeruginosa can degrade this molecule.”
Freeman, M. J., Eral, N. J., & Sauer, J. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1012492 · Cited by 13 · see citing works
Jones, R. S., Tu, C., Zhang, M., Qu, J., & Morris, M. E. (2019) · Molecular Pharmacology · doi:10.1124/mol.119.116731 · Cited by 13 · see citing works
“Also, Acod1 encodes for aconitate decarboxylase 1 and generates itaconate, a compound shown to play a role in antimicrobial activity of immune cells and indirect moderation of the tricarboxylate acid cycle (Luan and Medzhitov, 2016).”
BackgroundRole of mitochondria in regulating immune response during bacterial infection
Khan, S., Basu, S., Raj, D., & Lahiri, A. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.10.004 · Cited by 13 · see citing works
Itaconate and its derivatives as anti-pathogenic agents
Mazraani, R. A. A. D. A., Malys, N., & Malienė, V. (2025) · RSC Advances · doi:10.1039/d4ra08298b · Cited by 12 · see citing works
Hackett, E. E., & Sheedy, F. J. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00446 · Cited by 11 · see citing works
“ICL1 is part of the glyoxylate shunt which is thought to be an adaptation to low-glucose environments such as the phagolysosome (Luan and Medzhitov, 2016) allowing the bacterium to be fueled by 2carbon compounds (Lorenz and Fink, 2002).”
BackgroundItaconic Acid Increases the Efficacy of Tobramycin against Pseudomonas aeruginosa Biofilms
Ho, D., Rossi, C. D., Loretz, B., Murgia, X., & Lehr, C. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12080691 · Cited by 11 · see citing works
“Despite the antimicrobial properties and bacterial growth inhibition of IA [29], the normal growth of PA in the medium supplemented with IA reported here might be due to the presence of glucose in the PPGAS culture medium [30].”
BackgroundDimethyl Itaconate Inhibits Melanogenesis in B16F10 Cells
Yu, B.-Y., Ngo, H. H., Choi, W. J., & Keum, Y. (2023) · Antioxidants · doi:10.3390/antiox12030692 · Cited by 11 · see citing works
“It is now established that itaconate is a metabolite critical for antimicrobial defense, anti-inflammation, and mammalian immunity [19].”
Background2-Aminopyridine Analogs Inhibit Both Enzymes of the Glyoxylate Shunt in Pseudomonas aeruginosa
McVey, A. C., Bartlett, S., Kajbaf, M., Pellacani, A., Gatta, V., Tammela, P., Spring, D. R., & Welch, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072490 · Cited by 10 · see citing works
“The human enzyme, Irg1, synthesizes the ICL-inhibitory metabolite, itaconate, during macrophage activation [14].”
BackgroundFischer, N. L., Boyer, M. A., Bradley, W. P., Spruce, L. A., Fazelinia, H., & Shin, S. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.20.488957 · Cited by 10 · see citing works
“…immune responsive gene 1 (IRG1), which was suppressed by CBU1314, is a potent inhibitor of bacteria through production of itaconic acid (Luan & Medzhitov, 2016; Michelucci et al., 2013; Naujoks et al., 2016), and a previous study identified a ChIP-seq binding peak for CBU1314 close to…”
BackgroundItaconate: an antimicrobial metabolite of macrophages
Duncan, D., & Auclair, K. (2021) · Canadian Journal of Chemistry · doi:10.1139/cjc-2021-0117 · Cited by 9 · see citing works
Fuchs, A. L., Miller, I. R., Schiller, S. M., Ammons, M. C. B., Eilers, B. J., Tripet, B., & Copié, V. (2020) · Cells · doi:10.3390/cells9102260 · Cited by 9 · see citing works
“Although we did not detect itaconate, an antimicrobial metabolite known to inhibit succinate dehydrogenase [35,68,69], in any of our MΦ cell cultures; previous studies have determined that itaconate accumulation begins after 8–10 h of LPS stimulation in RAW264.”
BackgroundJack-of-all-trades: itaconate tolerizes NLRP3 inflammasome activation
Fischer, N. L., Shin, S., & Brodsky, I. E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108855 · Cited by 9 · see citing works
Breen, P., Zimbric, M., & Caverly, L. J. (2024) · PLoS ONE · doi:10.1371/journal.pone.0303516 · Cited by 7 · see citing works
“Specifically, itaconate inhibits multiple bacterial enzymes including iso-citrate lyase (ICL), succinate dehydrogenase (SDH) and propionyl-CoA carboxylase [40– 42, 45, 46].”
BackgroundInfluentialKorshoj, L. E., Shi, W., Duan, B., & Kielian, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.670931 · Cited by 8 · see citing works
“Citrate accumulation also leads to the generation of itaconate, which exerts bactericidal activity (73).”
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The coenzyme A biosynthetic pathway: A new tool for prodrug bioactivation
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“resensitize Salmonella enterica serovar Typhimurium to itaconate, an important macrophage metabolite with antimicrobial (via inhibition of isocitrate lyase or Icl)[140-142] and immunomodulatory activities[143-151].”
BackgroundLes métabokines, des médiateurs essentiels de l’immunité anti-infectieuse
Cezard, A., Monard, S., Bréa, D., Guillon, A., & Si‐Tahar, M. (2021) · médecine/sciences · doi:10.1051/medsci/2021031 · Cited by 8 · see citing works
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“For example, metabolites such as metabolically-derived itaconate, generated during the immune response and identified in our screening can regulate both the magnitude and duration of the immune response [62].”
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“Both itaconate, succinate, and lactate are generated specifically during the immune response and are essential for fuelling and supporting immune cell activation [44].”
Liu, Y., Zhang, P., Kong, W., Li, J., Yang, H., Bai, H., Fan, G., Cao, X., & Li, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1767601 · Cited by 7 · see citing works
Immunometabolites in viral infections: Action mechanism and function
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“64 Moreover, this antibacterial strategy exhibits greater specificity toward microbes than other agents like ROS and nitric oxide (NO), thereby reducing the risk of unintended harm.”
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The Impact of Krebs Cycle Intermediates on the Endocrine System and Immune System: A Comparison
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“Energy can also be used to synthesize the organic molecules required by the body for a wide range of functions, such as movement, digestion, and defense against disease-causing pathogens [16,70,71].”
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“10,12,13 14–17 However, to date, the effect of 4-OI on renal IRI-induced ERS remains unclear.”
BackgroundPseudomonas Persists by Feeding off Itaconate
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Metabolic control of microglia in health and disease
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Editorial: The Roles of Mitochondria in Immunity
Patil, N. K., Bohannon, J. K., Vachharajani, V., & McCall, C. E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.914639 · Cited by 4 · see citing works
- Authors
- Luan, H. H., & Medzhitov, R.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Medzhitov, Ruslan
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 24
- Issue
- 3
- Pages
- 379-387
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5024735
- OpenAlex
- W2519256061
- Cited by
- 130
- References
- 105
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 20 · 2022: 14 · 2021: 17 · 2020: 14 · 2019: 14 · 2018: 13 · 2017: 4
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR001863)
- National Institute of Allergy and Infectious Diseases (R37AI046688, T32AI007019)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034989)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- itaconate, antimicrobial defense, immunometabolism, innate immunity, bacterial metabolites, host-pathogen interaction
- MeSH terms
- Anti-Infective Agents, Energy Metabolism, Food, Immunity, Inflammation, Succinates, Metabolome
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