Cited by 1,264Immune cells in cancerCancer, Hypoxia, and MetabolismImmune responses and vaccinations

α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

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Liu, Pu-Ste, Wang, Haiping, Li, Xiaoyun, Chao, Tung, Teav, Tony, Christen, Stefan, Di Conza, Giusy, Cheng, Wan-Chen +9 more·2017·Nature Immunology

Abstract

Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

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Crossref · 10.1038/ni.3796

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Authors
Liu, P.-S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.-C., Chou, C.-H., Vavakova, M., Muret, C., Debackere, K., Mazzone, M., Huang, H.-D., Fendt, S.-M., Ivanisevic, J., & Ho, P.-C.
Affiliations
  • University of Lausanne (CH)
  • VIB-KU Leuven Center for Cancer Biology (BE)
  • National Yang Ming Chiao Tung University (TW)
  • KU Leuven (BE)
Corresponding author
Ho, Ping-Chih
Venue
Nature Immunology
Published
2017-07-17
Volume
18
Issue
9
Pages
985-994
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
OpenAlex
W2735344772
Cited by
1,264
References
46
Citations by year
2026: 210 · 2025: 213 · 2024: 192 · 2023: 153 · 2022: 144 · 2021: 125 · 2020: 110 · 2019: 62 · 2018: 45 · 2017: 10
FWCI
28.34
Type
journal article
Language
en
Open access
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • SERVAL (Université de Lausanne) (submittedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
alpha-ketoglutarate, glutamine metabolism, glutaminolysis, macrophage activation, M2 macrophages, M1 macrophages, fatty acid oxidation, JMJD3, epigenetic reprogramming, succinic acid, endotoxin tolerance, macrophage polarization
MeSH terms
Animals, Citric Acid Cycle, Fatty Acids, Glutamine, Glycolysis, Ketoglutaric Acids, Lipopolysaccharides, Macrophage Activation, Macrophages, Oxidation-Reduction, Oxidative Phosphorylation, Phenotype, NF-kappa B, Sequence Analysis, RNA, Succinic Acid, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Epigenesis, Genetic, Chromatin Immunoprecipitation, Mice, Metabolomics, Cellular Reprogramming

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