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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 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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“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).”
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Metadata
- 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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