Format

Send to

Choose Destination
Nat Commun. 2016 May 18;7:11635. doi: 10.1038/ncomms11635.

HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity.

Author information

1
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
2
Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo 106-0031, Japan.
3
PRESTO, JST, Saitama 332-0012, Japan.
4
Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
5
Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
6
Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 332-0012, Japan.
7
Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
8
Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
9
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1SZ, UK.
10
Department of Life Science and Medical BioScience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
11
Jichi Medical University, Tochigi 329-0498, Japan.

Abstract

In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.

PMID:
27189088
PMCID:
PMC4873978
DOI:
10.1038/ncomms11635
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center