Systemic silencing of Phd2 causes reversible immune regulatory dysfunction

Yamamoto, Atsushi, Hester, Joanna, Macklin, Philip S., Kawai, Kento, Uchiyama, Masateru, Biggs, Daniel, Bishop, Tammie, Bull, Katherine, Cheng, Xiaotong, Cawthorne, Eleano, Coleman, Mathew .L., Crockford, Tanya L., Davies, Ben, Dow, Lukas E., Goldin, Rob, Kranc, Kamil, Kudo, Hiromi, Lawson, Hannah, McAuliffe, James, Milward, Kate ORCID: https://orcid.org/0000-0003-3019-4443, Scudamore, Cheryl L., Soilleux, Elizabeth, Issa, Fadi, Ratcliffe, Peter J. and Pugh, Chris W. 2019. Systemic silencing of Phd2 causes reversible immune regulatory dysfunction. Journal of Clinical Investigation 129 (9) , pp. 3640-3656. 10.1172/JCI124099

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Abstract

Physiological effects of cellular hypoxia are sensed by prolyl hydroxylase (PHD) enzymes, which regulate HIFs. Genetic interventions on HIF/PHD pathways have revealed multiple phenotypes that extend the known biology of hypoxia. Recent studies have unexpectedly implicated 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, unphysiologically restricted, and difficult to time. To study these processes better, we developed recombinant mice that expressed tetracycline-regulated shRNAs broadly targeting the main components of the HIF/PHD pathway, permitting timed bidirectional intervention. We show that stabilization of HIF levels in adult mice through PHD2 enzyme silencing by RNA interference or inducible recombination of floxed alleles results in multilineage leukocytosis and features of autoimmunity. This phenotype was rapidly normalized on reestablishment 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 Treg markers from these mice revealed defective function and proinflammatory effects in vivo. We believe our findings reveal a new role for the PHD2/HIF2α pathway in the reversible regulation of T cell and immune activity.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article under the terms of the CC-BY Attribution 4.0 International license.
Publisher:	American Society for Clinical Investigation
ISSN:	0021-9738
Date of First Compliant Deposit:	5 April 2020
Date of Acceptance:	29 May 2019
Last Modified:	05 May 2023 08:30
URI:	https://orca.cardiff.ac.uk/id/eprint/130748

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