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dc.contributor.authorYamamoto, Atsushi
dc.contributor.authorHester, Joanna
dc.contributor.authorMacklin, Philip S
dc.contributor.authorKawai, Kento
dc.contributor.authorUchiyama, Masateru
dc.contributor.authorBiggs, Daniel
dc.contributor.authorBishop, Tammie
dc.contributor.authorBull, Katherine
dc.contributor.authorCheng, Xiaotong
dc.contributor.authorCawthorne, Eleanor
dc.contributor.authorColeman, Mathew L
dc.contributor.authorCrockford, Tanya L
dc.contributor.authorDavies, Ben
dc.contributor.authorDow, Lukas E
dc.contributor.authorGoldin, Rob
dc.contributor.authorKranc, Kamil
dc.contributor.authorKudo, Hiromi
dc.contributor.authorLawson, Hannah
dc.contributor.authorMcAuliffe, James
dc.contributor.authorMilward, Kate
dc.contributor.authorScudamore, Cheryl L
dc.contributor.authorSoilleux, Elizabeth
dc.contributor.authorIssa, Fadi
dc.contributor.authorRatcliffe, Peter J
dc.contributor.authorPugh, Chris W
dc.date.accessioned2019-12-21T00:30:34Z
dc.date.available2019-12-21T00:30:34Z
dc.date.issued2019-06-04
dc.identifier.issn0021-9738
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/300213
dc.description.abstractPhysiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes which regulate HIFs. Genetic interventions on HIF/PHD pathways reveal multiple phenotypes that extend the known biology of hypoxia. Recent studies unexpectedly implicate HIF in aspects of multiple immune and inflammatory pathways. However such studies are often limited by systemic lethal effects and/or use tissue-specific recombination systems, which are inherently irreversible, un-physiologically restricted and difficult to time. To study these processes better we developed recombinant mice which express tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bi-directional intervention. We have shown that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference, or inducible recombination of floxed alleles, results in multi-lineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on re-establishment of the hypoxia-sensing machinery when shRNA expression was discontinued. In both situations these effects were mediated principally through the Hif2a isoform. Assessment of cells bearing regulatory T cell markers from these mice revealed defective function and pro-inflammatory effects in vivo. We believe our findings have shown a new role for the PHD2/Hif2a couple in the reversible regulation of T cell and immune activity.
dc.format.mediumElectronic
dc.languageeng
dc.publisherAmerican Society for Clinical Investigation
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectMice, Transgenic
dc.subjectMice
dc.subjectSignal Transduction
dc.subjectRNA Interference
dc.subjectT-Lymphocytes, Regulatory
dc.subjectBasic Helix-Loop-Helix Transcription Factors
dc.subjectHypoxia-Inducible Factor-Proline Dioxygenases
dc.titleSystemic silencing of PHD2 causes reversible immune regulatory dysfunction.
dc.typeArticle
prism.endingPage3656
prism.issueIdentifier9
prism.publicationDate2019
prism.publicationNameJ Clin Invest
prism.startingPage3640
prism.volume129
dc.identifier.doi10.17863/CAM.47286
rioxxterms.versionofrecord10.1172/JCI124099
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-06-04
dc.contributor.orcidSoilleux, Elizabeth [0000-0002-4032-7249]
dc.identifier.eissn1558-8238
rioxxterms.typeJournal Article/Review
cam.issuedOnline2019-07-29


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