Cited by 930Immune responses and vaccinationsImmune cells in cancerImmune Response and Inflammation

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Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

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Arts, Rob J.W., Novakovic, Boris, ter Horst, Rob, Carvalho, Agostinho, Bekkering, Siroon, Lachmandas, Ekta, Rodrigues, Fernando, Silvestre, Ricardo, Cheng, Shih-Chin, Wang, Shuang-Yin, Habibi, Ehsan, Gonçalves, Luís G., Mesquita, Inês, Cunha, Cristina, van Laarhoven, Arjan, van de Veerdonk, Frank L., Williams, David L., van der Meer, Jos W.M., Logie, Colin, O'Neill, Luke A., Dinarello, Charles A., Riksen, Niels P., van Crevel, Reinout, Clish, Clary, Notebaart, Richard A., Joosten, Leo A.B., Stunnenberg, Hendrik G., Xavier, Ramnik J., Netea, Mihai G.·2016·Cell Metabolism

DOI 10.1016/j.cmet.2016.10.008PMC PMC5742541

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Abstract

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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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)
DOI: 10.1016/j.cmet.2016.10.008
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: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
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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Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity

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