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

    Semba, H., Takeda, N., Isagawa, T., Sugiura, Y., Honda, K., Wake, M., ... Komuro, I. (2016). HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nature Communications, 7, [11635]. https://doi.org/10.1038/ncomms11635

    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.
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