Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
Open accessAbstract
Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.
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Fumarate causes succination of mitochondrial aconitase ACO2, leading to truncation of the TCA cycle.
“Fumarate was shown to cause succination of the mitochondrial aconitase, ACO2, leading to an additional truncation of the TCA cycle86”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [86]
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Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · cited 1× · see citing works
“Citric acid cycle metabolites (e.g., fumarate and succinate) have previously been reported to regulate HIF1a stabilization by inhibiting hydroxylation and therefore stabilizing HIF1a (Koi- vunen et al., 2007; Tannahill et al., 2013).”
BackgroundSelf-citationCaspi, R., Billington, R., Ferrer, L., Foerster, H., Fulcher, C. A., Keseler, I. M., Kothari, A., Krummenacker, M., Latendresse, M., Mueller, L. A., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1164 · Cited by 3,395 · see citing works
Trained immunity: A program of innate immune memory in health and– disease
Netea, M. G., Joosten, L. A. B., Latz, E., Mills, K. H. G., Natoli, G., Stunnenberg, H. G., O’Neill, L. A. J., & Xavier, R. J. (2016) · Science · doi:10.1126/science.aaf1098 · Cited by 2,768 · see citing works
Self-citationMetaboAnalyst 3.0—making metabolomics more meaningful
Xia, J., Sinelnikov, I. V., Han, B., & Wishart, D. S. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv380 · Cited by 2,680 · see citing works
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Cheng, S.-C., Quintin, J., Cramer, R. A., Shepardson, K. M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E. J., Martens, J. H. A., Rao, N. A., Aghajanirefah, A., et al. (2014) · Science · doi:10.1126/science.1250684 · Cited by 2,224 · see citing works
Self-citationIDH mutation impairs histone demethylation and results in a block to cell differentiation
Lu, C., Ward, P. S., Kapoor, G. S., Rohle, D., Turcan, S., Abdel-Wahab, O., Edwards, C. R., Khanin, R., Figueroa, M. E., Melnick, A., et al. (2012) · Nature · doi:10.1038/nature10860 · Cited by 1,985 · see citing works
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
Saeed, S., Quintin, J., Kerstens, H. H. D., Rao, N. A., Aghajanirefah, A., Matarese, F., Cheng, S.-C., Ratter, J., Berentsen, K., van der Ent, M. A., et al. (2014) · Science · doi:10.1126/science.1251086 · Cited by 1,761 · see citing works
Self-citationKleinnijenhuis, J., Quintin, J., Preijers, F., Joosten, L. A. B., Ifrim, D. C., Saeed, S., Jacobs, C., van Loenhout, J., de Jong, D., Stunnenberg, H. G., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202870109 · Cited by 1,728 · see citing works
Self-citationTrained Immunity: A Memory for Innate Host Defense
Netea, M. G., Quintin, J., & van der Meer, J. W. M. (2011) · Cell Host & Microbe · doi:10.1016/j.chom.2011.04.006 · Cited by 1,697 · see citing works
Self-citationAdaptive Immune Features of Natural Killer Cells
Sun, J. C., Beilke, J., & Lanier, L. (2009) · Nature · doi:10.1038/nature07665 · Cited by 1,647 · see citing works
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,638 · see citing works
Amino acids and immune function
Li, P., Yin, Y., Li, D., Kim, S. W., & Wu, G. (2007) · British Journal Of Nutrition · doi:10.1017/s000711450769936x · Cited by 1,588 · see citing works
Systemic Acquired Resistance: Turning Local Infection into Global Defense
Fu, Z. Q., & Dong, X. (2013) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-042811-105606 · Cited by 1,528 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
Quintin, J., Saeed, S., Martens, J. H. A., Giamarellos-Bourboulis, E. J., Ifrim, D. C., Logie, C., Jacobs, L., Jansen, T., Kullberg, B.-J., Wijmenga, C., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.06.006 · Cited by 1,289 · see citing works
Self-citationCaspi, R., Altman, T., Billington, R., Dreher, K., Foerster, H., Fulcher, C. A., Holland, T. A., Keseler, I. M., Kothari, A., Kubo, A., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1103 · Cited by 1,204 · see citing works
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · cited 3× · see citing works
“KDMs of the JmjC and JmjD family need a-ketoglutarate as a cofactor for the demethylation process (Lu et al., 2012), whereas metabolites with a similar molecular structure, such as fumarate, can act as antagonizing factors (Lu et al., 2012; Xiao et al., 2012), thereby inhibiting demethylation.”
BackgroundBroad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
Cheng, S.-C., Scicluna, B. P., Arts, R. J. W., Gresnigt, M. S., Lachmandas, E., Giamarellos-Bourboulis, E. J., Kox, M., Manjeri, G. R., Wagenaars, J. A. L., Cremer, O. L., et al. (2016) · Nature Immunology · doi:10.1038/ni.3398 · Cited by 637 · see citing works
Self-citationMetformin as adjunct antituberculosis therapy
Singhal, A., Jie, L., Kumar, P., Hong, G. S., Leow, M. K.-S., Paleja, B., Tsenova, L., Kurepina, N., Chen, J., Zolezzi, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009885 · Cited by 547 · see citing works
Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610415200 · Cited by 521 · see citing works
IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 459 · see citing works
Reprogramming mitochondrial metabolism in macrophages as an anti‐inflammatory signal
Mills, E. L., & O'Neill, L. A. J. (2015) · European Journal of Immunology · doi:10.1002/eji.201445427 · Cited by 454 · see citing works
Self-citationSpecific memory within innate immune systems
Kurtz, J. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.02.001 · Cited by 394 · see citing works
King, Z. A., Dräger, A., Ebrahim, A., Sonnenschein, N., Lewis, N. E., & Palsson, B. Ø. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004321 · Cited by 370 · see citing works
O’Sullivan, T. E., Sun, J. C.-Y., & Lanier, L. L. (2015) · Immunity · doi:10.1016/j.immuni.2015.09.013 · Cited by 349 · see citing works
Tan, Z., Xie, N., Cui, H., Moellering, D. R., Abraham, E. H., Thannickal, V. J., & Liu, G. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402469 · Cited by 320 · see citing works
Keating, S. T., & El‐Osta, A. (2015) · Circulation Research · doi:10.1161/circresaha.116.303936 · Cited by 315 · see citing works
Plant innate immunity: An updated insight into defense mechanism
Muthamilarasan, M., & Prasad, M. (2013) · Journal of Biosciences · doi:10.1007/s12038-013-9302-2 · Cited by 309 · see citing works
Dysregulated metabolism contributes to oncogenesis
Hirschey, M. D., DeBerardinis, R. J., Diehl, A. M., Drew, J. E., Frezza, C., Green, M. F., Jones, L. W., Ko, Y. H., Le, A., Lea, M. A., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.10.002 · Cited by 306 · see citing works
Donohoe, D. R., & Bultman, S. J. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24054 · Cited by 296 · see citing works
den Bossche, J. V., Baardman, J., & de Winther, M. P. J. (2015) · Journal of Visualized Experiments · doi:10.3791/53424 · Cited by 274 · see citing works
Nonnutritive Effects of Glutamine
Roth, E. (2008) · Journal of Nutrition · doi:10.1093/jn/138.10.2025s · Cited by 255 · see citing works
Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
Jiang, Y., Qian, X., Shen, J., Wang, Y., Li, X., Liu, R., Xia, Y., Chen, Q., Peng, G., Lin, S.-Y., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3209 · Cited by 208 · see citing works
Schreiber, E. H., Harshman, K., Kemler, I., Malipiero, U., Schaffner, W., & Fontana, A. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.18.5495 · Cited by 163 · see citing works
Simple and cost-effective isolation of monocytes from buffy coats
Repnik, U., Knežević, M., & Jeras, M. (2003) · Journal of Immunological Methods · doi:10.1016/s0022-1759(03)00231-x · Cited by 163 · see citing works
Sikalidis, A. K. (2014) · Pathology & Oncology Research · doi:10.1007/s12253-014-9860-0 · Cited by 155 · see citing works
Signaling by small metabolites in systemic acquired resistance
Shah, J., Chaturvedi, R., Chowdhury, Z., Venables, B., & Petros, R. A. (2014) · The Plant Journal · doi:10.1111/tpj.12464 · Cited by 151 · see citing works
Robey, R. B., Weisz, J., Kuemmerle, N. B., Salzberg, A. C., Berg, A. S., Brown, D. G., Maurer, L. L., Palorini, R., Al‐Mulla, F., Al-Temaimi, R. A., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv037 · Cited by 138 · see citing works
Secombe, J., & Eisenman, R. N. (2007) · Cell Cycle · doi:10.4161/cc.6.11.4269 · Cited by 88 · see citing works
Extended Ischemia Prevents HIF1α Degradation at Reoxygenation by Impairing Prolyl-hydroxylation
Serra‐Pérez, A., Planas, A. M., Núñez-O’Mara, A., Berra, E., García‐Villoria, J., Ribes, A., & Santalucı́a, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101048 · Cited by 55 · see citing works
Tools and methods for studying the Drosophila JAK/STAT pathway
Chen, Q., Giedt, M. S., Tang, L., & Harrison, D. A. (2014) · Methods · doi:10.1016/j.ymeth.2014.03.023 · Cited by 32 · see citing works
Type 2 Diabetes Pharmacoepidemiology Update 2014: Safety Versus Efficacy
Singh, S. (2014) · Current Diabetes Reports · doi:10.1007/s11892-014-0563-4 · Cited by 6 · see citing works
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MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis
Chong, J., Soufan, O., Li, C., Caraus, I., Li, S., Bourque, G., Wishart, D. S., & Xia, J. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky310 · Cited by 3,577 · see citing works
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
Defining trained immunity and its role in health and disease
Netea, M. G., Domínguez-Andrés, J., Barreiro, L. B., Chavakis, T., Divangahi, M., Fuchs, E., Joosten, L. A. B., van der Meer, J. W. M., Mhlanga, M. M., Mulder, W. J. M., et al. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0285-6 · Cited by 2,690 · see citing works
Self-citationThe immunopathology of sepsis and potential therapeutic targets
van der Poll, T., van de Veerdonk, F. L., Scicluna, B. P., & Netea, M. G. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.36 · Cited by 1,957 · see citing works
Self-citationα-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
Liu, P.-S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.-C., Chou, C.-H., Vavakova, M., et al. (2017) · Nature Immunology · doi:10.1038/ni.3796 · Cited by 1,264 · see citing works
Macrophage Immunometabolism: Where Are We (Going)?
den Bossche, J. V., O'Neill, L. A. J., & Menon, D. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.03.001 · Cited by 1,162 · see citing works
Self-citationMitochondria are the powerhouses of immunity
Mills, E. L., Kelly, B., & O'Neill, L. A. J. (2017) · Nature Immunology · doi:10.1038/ni.3704 · Cited by 1,161 · see citing works
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Mitroulis, I., Ruppova, K., Wang, B., Chen, L.-S., Grzybek, M., Grinenko, T., Eugster, A., Troullinaki, M., Palladini, A., Kourtzelis, I., et al. (2018) · Cell · doi:10.1016/j.cell.2017.11.034 · Cited by 1,100 · see citing works
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Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,023 · see citing works
A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease
Baik, S. H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.-I., & Mook-Jung, I. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.005 · Cited by 843 · see citing works
Metabolic Induction of Trained Immunity through the Mevalonate Pathway
Bekkering, S., Arts, R. J. W., Novakovic, B., Kourtzelis, I., van der Heijden, C. D. C. C., Li, Y., Popa, C. D., ter Horst, R., van Tuijl, J., Netea-Maier, R. T., et al. (2018) · Cell · doi:10.1016/j.cell.2017.11.025 · Cited by 794 · see citing works
Self-citationMacrophages in inflammation, repair and regeneration
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Navigating metabolic pathways to enhance antitumour immunity and immunotherapy
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Liu, Y., Xu, R., Gu, H., Zhang, E., Qu, J., Cao, W., Huang, X., Yan, H., He, J., & Cai, Z. (2021) · Biomarker Research · doi:10.1186/s40364-020-00251-y · Cited by 657 · see citing works
Glycolysis – a key player in the inflammatory response
Soto‐Heredero, G., Heras, M. M. G. D. L., Gabandé‐Rodríguez, E., Oller, J., & Mittelbrunn, M. (2020) · FEBS Journal · doi:10.1111/febs.15327 · Cited by 645 · see citing works
A timeline of tumour-associated macrophage biology
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Regulation of macrophage immunometabolism in atherosclerosis
Koelwyn, G. J., Corr, E. M., Erbay, E., & Moore, K. J. (2018) · Nature Immunology · doi:10.1038/s41590-018-0113-3 · Cited by 557 · see citing works
The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery
Stunnenberg, H. G., Abrignani, S., Adams, D. J., de Almeida, M., Altucci, L., Amin, V. R., Amit, I., Antonarakis, S. E., Aparicio, S. A. J. R., Arima, T., et al. (2016) · Cell · doi:10.1016/j.cell.2016.11.007 · Cited by 485 · see citing works
Self-citationTrained immunity — basic concepts and contributions to immunopathology
Ochando, J., Mulder, W. J. M., Madsen, J. C., Netea, M. G., & Duivenvoorden, R. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00633-5 · Cited by 474 · see citing works
Self-citationChronic inflammation and the hallmarks of aging
Baechle, J. J., Chen, N., Makhijani, P., Winer, S., Furman, D., & Winer, D. A. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101755 · Cited by 471 · see citing works
Therapeutic targeting of trained immunity
Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A., & Netea, M. G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0025-4 · Cited by 446 · see citing works
Self-citationKrebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444 · see citing works
Self-citationEnergy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 438 · see citing works
Self-citationCoupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Self-citationDomínguez‐Andrés, J., Novakovic, B., Li, Y., Scicluna, B. P., Gresnigt, M. S., Arts, R. J. W., Oosting, M., Moorlag, S. J. C. F. M., Groh, L. A., Zwaag, J., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.003 · Cited by 394 · see citing works
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Epigenetic regulation of the innate immune response to infection
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Patel, C. H., Leone, R. D., Horton, M. R., & Powell, J. D. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0032-5 · Cited by 307 · see citing works
Fanucchi, S., Fok, E. T., Dalla, E., Shibayama, Y., Börner, K., Chang, E. Y., Stoychev, S., Imakaev, M., Grimm, D., Wang, K., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0298-2 · Cited by 296 · see citing works
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Diskin, C., & Pålsson‐McDermott, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00270 · Cited by 292 · see citing works
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Bailey, J. D., Diotallevi, M., NICOL, T., McNeill, E., Shaw, A., Chuaiphichai, S., Hale, A., Starr, A., Nandi, M., Stylianou, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.018 · Cited by 266 · see citing works
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Wu, M.-Y., & Lu, J. (2019) · Cells · doi:10.3390/cells9010070 · Cited by 266 · see citing works
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Cabău, G., Crișan, T. O., Klück, V., Popp, R. A., & Joosten, L. A. B. (2019) · Immunological Reviews · doi:10.1111/imr.12833 · Cited by 262 · see citing works
Self-citationIntrauterine programming of obesity and type 2 diabetes
Fernandez‐Twinn, D. S., Hjort, L., Novakovic, B., Ozanne, S. E., & Saffery, R. (2019) · Diabetologia · doi:10.1007/s00125-019-4951-9 · Cited by 257 · see citing works
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Groh, L. A., Keating, S. T., Joosten, L. A. B., Netea, M. G., & Riksen, N. P. (2017) · Seminars in Immunopathology · doi:10.1007/s00281-017-0656-7 · Cited by 255 · see citing works
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Neher, J. J., & Cunningham, C. M. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.02.001 · Cited by 255 · see citing works
Glutamine Metabolism in Macrophages: A Novel Target for Obesity/Type 2 Diabetes
Ren, W., Xia, Y., Chen, S., Wu, G., Bazer, F. W., Zhou, B., Tan, B., Zhu, G., Deng, J., & Yin, Y. (2018) · Advances in Nutrition · doi:10.1093/advances/nmy084 · Cited by 251 · see citing works
Mitochondrial function in immune cells in health and disease
Faas, M. M., & de Vos, P. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165845 · Cited by 246 · see citing works
Kieler, M., Hofmann, M., & Schabbauer, G. (2021) · FEBS Journal · doi:10.1111/febs.15715 · Cited by 246 · see citing works
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production
Hooftman, A., Peace, C. G., Ryan, D. G., Day, E. A., Yang, M. H., McGettrick, A. F., Yin, M., Montano, E. N., Huo, L., Toller-Kawahisa, J. E., et al. (2023) · Nature · doi:10.1038/s41586-023-05720-6 · Cited by 246 · see citing works
Self-citationTricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Choi, I., Son, H., & Baek, J.-H. (2021) · Life · doi:10.3390/life11010069 · Cited by 246 · see citing works
Dectin-1 Signaling Update: New Perspectives for Trained Immunity
Mata-Martínez, P., Bergón-Gutiérrez, M., & del Fresno, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.812148 · Cited by 243 · see citing works
Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory
Negi, S., Das, D. K., Pahari, S., Nadeem, S., & Agrewala, J. N. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02441 · Cited by 240 · see citing works
Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses
Chen, L., Morcelle, C., Cheng, Z., Chen, X., Xu, Y., Gao, Y., Song, J., Li, Z., Smith, M. D., Shi, M., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00853-8 · Cited by 228 · see citing works
2-Oxoglutarate-dependent dioxygenases in cancer
Losman, J.-A., Koivunen, P., & Kaelin, W. G. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00303-3 · Cited by 225 · see citing works
Trained immunity: adaptation within innate immune mechanisms
Domínguez‐Andrés, J., dos Santos, J. C., Bekkering, S., Mulder, W. J. M., van der Meer, J. W. M., Riksen, N. P., Joosten, L. A. B., & Netea, M. G. (2022) · Physiological Reviews · doi:10.1152/physrev.00031.2021 · Cited by 216 · see citing works
Self-citationSchnitzler, J. G., Hoogeveen, R. M., Ali, L., Prange, K. H. M., Waissi, F., van Weeghel, M., Bachmann, J. C., Versloot, M., Borrelli, M. J., Yeang, C., et al. (2020) · Circulation Research · doi:10.1161/circresaha.119.316206 · Cited by 213 · see citing works
Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance
Sheu, K. M., & Hoffmann, A. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-031555 · Cited by 209 · see citing works
Li, X., Gong, W., Wang, H., Li, T., Attri, K. S., Lewis, R. E., Kalil, A. C., Bhinderwala, F., Powers, R., Yin, G., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.01.007 · Cited by 204 · see citing works
Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer
van Puffelen, J. H., Keating, S. T., Oosterwijk, E., van der Heijden, A. G., Netea, M. G., Joosten, L. A. B., & Vermeulen, S. H. H. M. (2020) · Nature Reviews Urology · doi:10.1038/s41585-020-0346-4 · Cited by 204 · see citing works
Self-citationDu, L., Lin, L., Li, Q., Liu, K., Huang, Y., Wang, X., Cao, K., Chen, X., Cao, W., Li, F., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.006 · Cited by 201 · see citing works
Cytokine-like Roles for Metabolites in Immunity
Zasłona, Z., & O'Neill, L. A. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.002 · Cited by 198 · see citing works
Self-citationMetabolic Reprogramming in Immune Response and Tissue Inflammation
Sun, L., Yang, X., Yuan, Z., & Wang, H. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314037 · Cited by 198 · see citing works
Current Understanding of IL-37 in Human Health and Disease
Su, Z., & Tao, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.696605 · Cited by 197 · see citing works
Stienstra, R., Netea-Maier, R. T., Riksen, N. P., Joosten, L. A. B., & Netea, M. G. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.001 · Cited by 194 · see citing works
Self-citationMetabolic Reprogramming Induces Macrophage Polarization in the Tumor Microenvironment
Wang, S., Liu, G., Li, Y., & Pan, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.840029 · Cited by 194 · see citing works
Self-citationAlternative Pathways of IL-1 Activation, and Its Role in Health and Disease
Pyrillou, K., Burzynski, L. C., & Clarke, M. C. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613170 · Cited by 188 · see citing works
Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory
Ziogas, A., Novakovic, B., Ventriglia, L., Galang, N., Tran, K. A., Li, W., Matzaraki, V., van Unen, N., Schlüter, T., Ferreira, A. V., et al. (2025) · Cell · doi:10.1016/j.cell.2025.03.048 · Cited by 187 · see citing works
Self-citationBernard, K. F., Logsdon, N. J., Benavides, G. A., Sanders, Y. Y., Zhang, J., Darley-Usmar, V. M., & Thannickal, V. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000444 · Cited by 178 · see citing works
Long-term reprogramming of the innate immune system
Domínguez‐Andrés, J., & Netea, M. G. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr0318-104r · Cited by 176 · see citing works
Self-citationThe Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders
Arts, R. J. W., Joosten, L. A. B., & Netea, M. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00298 · Cited by 175 · see citing works
Self-citationKeating, S. T., Groh, L. A., van der Heijden, C. D. C. C., Rodriguez, H., dos Santos, J. C., Fanucchi, S., Okabe, J., Kaipananickal, H., van Puffelen, J. H., Helder, L. S., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107548 · Cited by 173 · see citing works
Self-citationActivation of immune signals during organ transplantation
Li, Q., & Lan, P. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01377-9 · Cited by 173 · see citing works
Perinatal and Early-Life Nutrition, Epigenetics, and Allergy
Acevedo, N., Alhamwe, B. A., Caraballo, L. R., Ding, M., Ferrante, A., Garn, H., Garssen, J., Hii, C. S. T., Irvine, J., Llinás-Caballero, K., et al. (2021) · Nutrients · doi:10.3390/nu13030724 · Cited by 172 · see citing works
Bekkering, S., Stiekema, L. C. A., Moens, S. J. B., Verweij, S. L., Novakovic, B., Prange, K. H. M., Versloot, M., van Lennep, J. E. R., Stunnenberg, H. G., de Winther, M. P. J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.014 · Cited by 170 · see citing works
Self-citationImmunometabolic control of trained immunity
Riksen, N. P., & Netea, M. G. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100897 · Cited by 170 · see citing works
Self-citationCatecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo
van der Heijden, C. D. C. C., Groh, L. A., Keating, S. T., Kaffa, C., Noz, M. P., Kersten, S., van Herwaarden, A. E., Hoischen, A., Joosten, L. A. B., Timmers, H. J. L. M., et al. (2020) · Circulation Research · doi:10.1161/circresaha.119.315800 · Cited by 167 · see citing works
Self-citationGe, J., Cui, H., Xie, N., Banerjee, S., Guo, S., Dubey, S., Barnes, S., & Liu, G. (2018) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0238oc · Cited by 166 · see citing works
The Complexity of Fungal β-Glucan in Health and Disease: Effects on the Mononuclear Phagocyte System
Camilli, G., Tabouret, G., & Quintin, J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00673 · Cited by 158 · see citing works
Epigenetic Remodeling in Innate Immunity and Inflammation
Zhang, Q., & Cao, X. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-093019-123619 · Cited by 158 · see citing works
Trained Immunity Confers Broad-Spectrum Protection Against Bacterial Infections
Ciarlo, E., Heinonen, T., Théroude, C., Asgari, F., Roy, D. L., Netea, M. G., & Roger, T. (2019) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiz692 · Cited by 157 · see citing works
Self-citationTrained immunity: General and emerging concepts
Vuscan, P., Kischkel, B., Joosten, L. A. B., & Netea, M. G. (2024) · Immunological Reviews · doi:10.1111/imr.13326 · Cited by 156 · see citing works
Self-citationSaaoud, F., Liu, L., Xu, K., Cueto, R., Shao, Y., Lu, Y., Sun, Y., Snyder, N. W., Wu, S., Yang, L., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.158183 · Cited by 153 · see citing works
Self-citationInduction of innate immune memory: the role of cellular metabolism
Domínguez‐Andrés, J., Joosten, L. A. B., & Netea, M. G. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.001 · Cited by 152 · see citing works
Self-citationMetabolic reprogramming, oxidative stress, and pulmonary hypertension
Pokharel, M. D., Marciano, D. P., Fu, P., Franco, M. C., Unwalla, H. J., Tieu, K., Fineman, J. R., Wang, T., & Black, S. M. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102797 · Cited by 151 · see citing works
Krebs cycle rewired for macrophage and dendritic cell effector functions
Ryan, D. G., & O'Neill, L. A. J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12744 · Cited by 150 · see citing works
Self-citationMetabolic programs tailor T cell immunity in viral infection, cancer, and aging
Møller, S. H., Hsueh, P., Yu, Y.-R., Zhang, L., & Ho, P. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.003 · Cited by 148 · see citing works
Leentjens, J., Bekkering, S., Joosten, L. A. B., Netea, M. G., Burgner, D. P., & Riksen, N. P. (2018) · Circulation Research · doi:10.1161/circresaha.117.312465 · Cited by 146 · see citing works
Self-citationRewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
Keating, S. T., Groh, L. A., Thiem, K., Bekkering, S., Li, Y., Matzaraki, V., van der Heijden, C. D. C. C., van Puffelen, J. H., Lachmandas, E., Jansen, T., et al. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01915-w · Cited by 145 · see citing works
Self-citationTrained Immunity Carried by Non-immune Cells
Hamada, A., Torre, C., Drancourt, M., & Ghigo, É. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.03225 · Cited by 144 · see citing works
IL-1 family cytokines in inflammation and immunity
Garlanda, C., Ceglie, I. D., & Jaillon, S. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01358-8 · Cited by 143 · see citing works
Kouidhi, S., Elgaaïed, A. B., & Chouaı̈b, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00270 · Cited by 138 · see citing works
Nuclear-Mitochondrial Interactions
Walker, B. R., & Moraes, C. T. (2022) · Biomolecules · doi:10.3390/biom12030427 · Cited by 136 · see citing works
Targeting innate immunity for tuberculosis vaccination
Khader, S. A., Divangahi, M., Hanekom, W. A., Hill, P. C., Maeurer, M. J., Makar, K. W., Mayer-Barber, K. D., Mhlanga, M. M., Nemes, E., Schlesinger, L. S., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci128877 · Cited by 134 · see citing works
Self-citationModulation of Macrophage Immunometabolism: A New Approach to Fight Infections
Gauthier, T., & Chen, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.780839 · Cited by 134 · see citing works
Human Dendritic Cell Subsets Undergo Distinct Metabolic Reprogramming for Immune Response
Basit, F., Mathan, T. S. M., Sancho, D., & de Vries, I. J. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02489 · Cited by 133 · see citing works
Plat, J., Baumgartner, S., Vanmierlo, T., Lütjohann, D., Calkins, K. L., Burrin, D. G., Guthrie, G. J., Thijs, C. T., Velde, A. A. T., Vreugdenhil, A. C. E., et al. (2019) · Progress in Lipid Research · doi:10.1016/j.plipres.2019.02.003 · Cited by 133 · see citing works
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Jentho, E., Ruiz-Moreno, C., Novakovic, B., Kourtzelis, I., Megchelenbrink, W., Martins, R., Chavakis, T., Soares, M. P., Kalafati, L., Guerra, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2102698118 · Cited by 133 · see citing works
Self-citationMethionine metabolism influences genomic architecture and gene expression through H3K4me3 peak width
Dai, Z., Mentch, S. J., Gao, X., Nichenametla, S. N., & Locasale, J. W. (2018) · Nature Communications · doi:10.1038/s41467-018-04426-y · Cited by 132 · see citing works
- Authors
- Arts, R. J. W., Novakovic, B., ter Horst, R., Carvalho, A., Bekkering, S., Lachmandas, E., Rodrigues, F., Silvestre, R., Cheng, S.-C., Wang, S.-Y., Habibi, E., Gonçalves, L. G., Mesquita, I., Cunha, C., van Laarhoven, A., van de Veerdonk, F. L., Williams, D. L., van der Meer, J. W. M., Logie, C., O'Neill, L. A., Dinarello, C. A., Riksen, N. P., van Crevel, R., Clish, C., Notebaart, R. A., Joosten, L. A. B., Stunnenberg, H. G., Xavier, R. J., & Netea, M. G.
- Affiliations
- Radboud University Medical Center (NL)
- Radboud University Nijmegen (NL)
- University of Minho (PT)
- National Tsing Hua University (TW)
- Instituto de Tecnologia Química e Biológica António Xavier (PT)
- East Tennessee State University (US)
- Trinity College Dublin (IE)
- Broad Institute (US)
- Corresponding author
- Arts, Rob J.W.
- ORCID
- Arts, Rob J.W.
- Novakovic, Boris
- Carvalho, Agostinho
- Bekkering, Siroon
- Rodrigues, Fernando
- Silvestre, Ricardo
- Cheng, Shih-Chin
- Wang, Shuang-Yin
- Habibi, Ehsan
- Gonçalves, Luís G.
- Mesquita, Inês
- Cunha, Cristina
- Williams, David L.
- Logie, Colin
- O'Neill, Luke A.
- Dinarello, Charles A.
- Riksen, Niels P.
- Clish, Clary
- Notebaart, Richard A.
- Joosten, Leo A.B.
- Stunnenberg, Hendrik G.
- Xavier, Ramnik J.
- Netea, Mihai G.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 24
- Issue
- 6
- Pages
- 807-819
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5742541
- OpenAlex
- W2557169014
- Cited by
- 930
- References
- 42
- Citations by year
- 2026: 134 · 2025: 120 · 2024: 101 · 2023: 81 · 2022: 118 · 2021: 111 · 2020: 108 · 2019: 66 · 2018: 62 · 2017: 28 · 2016: 1
- FWCI
- 31.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by-nc-nd)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by-nc-nd)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
- Funders
- ERC Consolidator (310372)
- Spinoza
- Netherlands Organization for Scientific Research
- NHMRC
- CJ Martin Early Career Fellowship
- Dr. Dekker
- Netherlands Heart Foundation (2012T051)
- H2020
- European Union (667837)
- Fundação para a Ciência e Tecnologia (IF/00735/2014, IF/00021/2014, RECI/BBB-BQB/0230/2012, SFRH/BPD/96176/2013)
- FCT (RECI/BBB-BQB/0230/2012)
- Programa Operacional Regional do Norte (ON.2—O Novo Norte)
- Quadro de Referência Estratégico Nacional
- Fundo Europeu de Desenvolvimento Regional
- Projeto Estratégico (LA 26 – 2013–2014 (PEst-C/SAU/LA0026/2013)
- NIH (DK43351, DK097485, GM53522, GM083016, GM119197, C06RR0306551)
- Helmsley Trust
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- trained immunity, glutaminolysis, fumarate accumulation, monocytes, β-glucan, epigenetic reprogramming, cholesterol biosynthesis, glycolysis, TCA cycle, immunometabolism, epigenetic rewiring
- MeSH terms
- Cholesterol, Fumarates, Glucose, Glutamine, Glycolysis, Humans, Immune Tolerance, Immunity, Innate, Macrophages, Models, Biological, Pentose Phosphate Pathway, Epigenesis, Genetic, Hypoxia-Inducible Factor 1, alpha Subunit, Proteolysis
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