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 journalArticle

64 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

Fingerprint

glycolysis
macrophages
Macrophages
Glycolysis
adenosine triphosphate
glucose
Adenosine Triphosphate
monocytes
pyruvates
Glucose
Pseudopodia
oxidase
cytochromes
hypoxia
metabolism
Electron Transport Complex IV
Pyruvic Acid
Metabolism
entry
encounters

ASJC Scopus subject areas

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

Cite this

HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. / Semba, Hiroaki; Takeda, Norihiko; Isagawa, Takayuki; Sugiura, Yuki; Honda, Kurara; Wake, Masaki; Miyazawa, Hidenobu; Yamaguchi, Yoshifumi; Miura, Masayuki; Jenkins, Dana M R; Choi, Hyunsung; Kim, Jung Whan; Asagiri, Masataka; Cowburn, Andrew S.; Abe, Hajime; Soma, Katsura; Koyama, Katsuhiro; Katoh, Manami; Sayama, Keimon; Goda, Nobuhito; Johnson, Randall S.; Manabe, Ichiro; Nagai, Ryozo; Komuro, Issei.

In: Nature Communications, Vol. 7, 11635, 18.05.2016.

Research output: Contribution to journalArticle

Semba, H, Takeda, N, Isagawa, T, Sugiura, Y, Honda, K, Wake, M, Miyazawa, H, Yamaguchi, Y, Miura, M, Jenkins, DMR, Choi, H, Kim, JW, Asagiri, M, Cowburn, AS, Abe, H, Soma, K, Koyama, K, Katoh, M, Sayama, K, Goda, N, Johnson, RS, Manabe, I, Nagai, R & Komuro, I 2016, 'HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity', Nature Communications, vol. 7, 11635. https://doi.org/10.1038/ncomms11635
Semba, Hiroaki ; Takeda, Norihiko ; Isagawa, Takayuki ; Sugiura, Yuki ; Honda, Kurara ; Wake, Masaki ; Miyazawa, Hidenobu ; Yamaguchi, Yoshifumi ; Miura, Masayuki ; Jenkins, Dana M R ; Choi, Hyunsung ; Kim, Jung Whan ; Asagiri, Masataka ; Cowburn, Andrew S. ; Abe, Hajime ; Soma, Katsura ; Koyama, Katsuhiro ; Katoh, Manami ; Sayama, Keimon ; Goda, Nobuhito ; Johnson, Randall S. ; Manabe, Ichiro ; Nagai, Ryozo ; Komuro, Issei. / HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. In: Nature Communications. 2016 ; Vol. 7.
@article{406cbfdac0dc42aeb2dc141d509fbdb0,
title = "HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity",
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.",
author = "Hiroaki Semba and Norihiko Takeda and Takayuki Isagawa and Yuki Sugiura and Kurara Honda and Masaki Wake and Hidenobu Miyazawa and Yoshifumi Yamaguchi and Masayuki Miura and Jenkins, {Dana M R} and Hyunsung Choi and Kim, {Jung Whan} and Masataka Asagiri and Cowburn, {Andrew S.} and Hajime Abe and Katsura Soma and Katsuhiro Koyama and Manami Katoh and Keimon Sayama and Nobuhito Goda and Johnson, {Randall S.} and Ichiro Manabe and Ryozo Nagai and Issei Komuro",
year = "2016",
month = "5",
day = "18",
doi = "10.1038/ncomms11635",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity

AU - Semba, Hiroaki

AU - Takeda, Norihiko

AU - Isagawa, Takayuki

AU - Sugiura, Yuki

AU - Honda, Kurara

AU - Wake, Masaki

AU - Miyazawa, Hidenobu

AU - Yamaguchi, Yoshifumi

AU - Miura, Masayuki

AU - Jenkins, Dana M R

AU - Choi, Hyunsung

AU - Kim, Jung Whan

AU - Asagiri, Masataka

AU - Cowburn, Andrew S.

AU - Abe, Hajime

AU - Soma, Katsura

AU - Koyama, Katsuhiro

AU - Katoh, Manami

AU - Sayama, Keimon

AU - Goda, Nobuhito

AU - Johnson, Randall S.

AU - Manabe, Ichiro

AU - Nagai, Ryozo

AU - Komuro, Issei

PY - 2016/5/18

Y1 - 2016/5/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84970028181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84970028181&partnerID=8YFLogxK

U2 - 10.1038/ncomms11635

DO - 10.1038/ncomms11635

M3 - Article

C2 - 27189088

AN - SCOPUS:84970028181

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11635

ER -