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

Hiroaki Semba, Norihiko Takeda (), Takayuki Isagawa, Yuki Sugiura, Kurara Honda, Masaki Wake, Hidenobu Miyazawa, Yoshifumi Yamaguchi, Masayuki Miura, Dana M. R. Jenkins, Hyunsung Choi, Jung-whan Kim, Masataka Asagiri, Andrew S. Cowburn, Hajime Abe, Katsura Soma, Katsuhiro Koyama, Manami Katoh, Keimon Sayama, Nobuhito Goda, Randall S. Johnson, Ichiro Manabe, Ryozo Nagai and Issei Komuro
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Hiroaki Semba: Graduate School of Medicine, The University of Tokyo
Norihiko Takeda: Graduate School of Medicine, The University of Tokyo
Takayuki Isagawa: Graduate School of Medicine, The University of Tokyo
Yuki Sugiura: PRESTO, JST
Kurara Honda: Keio University School of Medicine
Masaki Wake: Graduate School of Medicine, The University of Tokyo
Hidenobu Miyazawa: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Yoshifumi Yamaguchi: PRESTO, JST
Masayuki Miura: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Dana M. R. Jenkins: The University of Texas at Dallas
Hyunsung Choi: The University of Texas at Dallas
Jung-whan Kim: The University of Texas at Dallas
Masataka Asagiri: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University
Andrew S. Cowburn: Development and Neuroscience, University of Cambridge
Hajime Abe: Graduate School of Medicine, The University of Tokyo
Katsura Soma: Graduate School of Medicine, The University of Tokyo
Katsuhiro Koyama: Graduate School of Medicine, The University of Tokyo
Manami Katoh: Graduate School of Medicine, The University of Tokyo
Keimon Sayama: School of Advanced Science and Engineering, Waseda University
Nobuhito Goda: School of Advanced Science and Engineering, Waseda University
Randall S. Johnson: Development and Neuroscience, University of Cambridge
Ichiro Manabe: Graduate School of Medicine, The University of Tokyo
Ryozo Nagai: Jichi Medical University
Issei Komuro: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11635

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