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α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming.
Journal article

α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming.

  • Liu PS Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Wang H Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Li X Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Chao T Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Teav T Metabolomics Unit, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • Christen S Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Di Conza G Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Cheng WC Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Chou CH Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan.
  • Vavakova M Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Muret C Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
  • Debackere K Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
  • Mazzone M Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
  • Huang HD Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan.
  • Fendt SM Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
  • Ivanisevic J Metabolomics Unit, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
  • Ho PC Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
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  • 2017-07-18
Published in:
  • Nature immunology. - 2017
Animals
Cellular Reprogramming
Chromatin Immunoprecipitation
Citric Acid Cycle
Epigenesis, Genetic
Fatty Acids
Gene Expression Profiling
Glutamine
Glycolysis
Ketoglutaric Acids
Lipopolysaccharides
Macrophage Activation
Macrophages
Metabolomics
Mice
NF-kappa B
Oxidation-Reduction
Oxidative Phosphorylation
Phenotype
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, RNA
Succinic Acid
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/246365
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