Format

Send to

Choose Destination
Nat Immunol. 2017 Sep;18(9):985-994. doi: 10.1038/ni.3796. Epub 2017 Jul 17.

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

Author information

1
Department of Fundamental Oncology, Faculty of Biology and Medicine, University of Lausanne, Epalinges, Switzerland.
2
Ludwig Lausanne Branch, Epalinges, Switzerland.
3
Metabolomics Unit, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
4
Laboratory of Cellular Metabolism and Metabolic Regulation, Center for Cancer Biology, VIB, Leuven, Belgium.
5
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
6
Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin-Chu, Taiwan.
7
Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.
8
Laboratory of Tumor Inflammation and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium.
9
Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium.

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.

PMID:
28714978
DOI:
10.1038/ni.3796
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center