Systemic silencing of PHD2 causes reversible immune regulatory dysfunction.
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Authors
Yamamoto, Atsushi
Hester, Joanna
Macklin, Philip S
Kawai, Kento
Uchiyama, Masateru
Biggs, Daniel
Bishop, Tammie
Bull, Katherine
Cheng, Xiaotong
Cawthorne, Eleanor
Coleman, Mathew L
Crockford, Tanya L
Davies, Ben
Dow, Lukas E
Goldin, Rob
Kranc, Kamil
Kudo, Hiromi
Lawson, Hannah
McAuliffe, James
Milward, Kate
Scudamore, Cheryl L
Issa, Fadi
Ratcliffe, Peter J
Pugh, Chris W
Publication Date
2019-06-04Journal Title
J Clin Invest
ISSN
0021-9738
Publisher
American Society for Clinical Investigation
Volume
129
Issue
9
Pages
3640-3656
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Yamamoto, A., Hester, J., Macklin, P. S., Kawai, K., Uchiyama, M., Biggs, D., Bishop, T., et al. (2019). Systemic silencing of PHD2 causes reversible immune regulatory dysfunction.. J Clin Invest, 129 (9), 3640-3656. https://doi.org/10.1172/JCI124099
Abstract
Physiological 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.
Keywords
Animals, Mice, Transgenic, Mice, Signal Transduction, RNA Interference, T-Lymphocytes, Regulatory, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor-Proline Dioxygenases
Identifiers
External DOI: https://doi.org/10.1172/JCI124099
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300213
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