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 GodaRandall S. Johnson, Ichiro Manabe, Ryozo Nagai, Issei Komuro

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

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.

Original languageEnglish
Article number11635
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 May 18

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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