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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo 106-0031, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Semba
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|PRESTO, JST, Saitama 332-0012, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Takeda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Isagawa
authors.affiliation: PRESTO, JST, Saitama 332-0012, Japan.|Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugiura
authors.affiliation: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kurara
authors.initials: K
authors.lastname: Honda
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Wake
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Miyazawa
authors.affiliation: PRESTO, JST, Saitama 332-0012, Japan.|Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yoshifumi
authors.identifier: 0000-0001-7340-4557
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8655, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 332-0012, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Dana M R
authors.initials: DM
authors.lastname: Jenkins
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas 75080, USA.
authors.forename: Jung-Whan
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Asagiri
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1SZ, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Soma
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Koyama
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Manami
authors.initials: M
authors.lastname: Katoh
authors.affiliation: Department of Life Science and Medical BioScience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Keimon
authors.initials: K
authors.lastname: Sayama
authors.affiliation: Department of Life Science and Medical BioScience, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1SZ, UK.
authors.forename: Randall S
authors.identifier: 0000-0002-4084-6639
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003999:Dichloroacetic Acid; D003576:Electron Transport Complex IV / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D003576:Electron Transport Complex IV; D017346:Protein Serine-Threonine Kinases; D005947:Glucose