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dc.contributor.authorSemba, Hiroaki
dc.contributor.authorTakeda, Norihiko
dc.contributor.authorIsagawa, Takayuki
dc.contributor.authorSugiura, Yuki
dc.contributor.authorHonda, Kurara
dc.contributor.authorWake, Masaki
dc.contributor.authorMiyazawa, Hidenobu
dc.contributor.authorYamaguchi, Yoshifumi
dc.contributor.authorMiura, Masayuki
dc.contributor.authorJenkins, Dana MR
dc.contributor.authorChoi, Hyunsung
dc.contributor.authorKim, Jung-Whan
dc.contributor.authorAsagiri, Masataka
dc.contributor.authorCowburn, Andrew
dc.contributor.authorAbe, Hajime
dc.contributor.authorSoma, Katsura
dc.contributor.authorKoyama, Katsuhiro
dc.contributor.authorKatoh, Manami
dc.contributor.authorSayama, Keimon
dc.contributor.authorGoda, Nobuhito
dc.contributor.authorJohnson, Randall
dc.contributor.authorManabe, Ichiro
dc.contributor.authorNagai, Ryozo
dc.contributor.authorKomuro, Issei
dc.date.accessioned2018-05-04T14:04:12Z
dc.date.available2018-05-04T14:04:12Z
dc.date.issued2016-05-18
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275583
dc.description.abstractIn 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.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumor
dc.subjectMacrophages
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectElectron Transport Complex IV
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectGlucose
dc.subjectCell Movement
dc.subjectGlycolysis
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit
dc.subjectPrimary Cell Culture
dc.subjectDichloroacetic Acid
dc.subjectHypoxia
dc.subjectPyruvate Dehydrogenase (Acetyl-Transferring) Kinase
dc.titleHIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity.
dc.typeArticle
prism.publicationDate2016
prism.publicationNameNat Commun
prism.startingPage11635
prism.volume7
dc.identifier.doi10.17863/CAM.22825
dcterms.dateAccepted2016-04-14
rioxxterms.versionofrecord10.1038/ncomms11635
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-05-18
dc.contributor.orcidYamaguchi, Yoshifumi [0000-0001-7340-4557]
dc.contributor.orcidCowburn, Andrew [0000-0001-9145-4275]
dc.contributor.orcidJohnson, Randall [0000-0002-4084-6639]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idWellcome Trust (092738/Z/10/Z)
cam.issuedOnline2016-05-18
cam.orpheus.successThu Jan 30 13:00:25 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International