Year: 2019
Type: article
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.
DOI: 10.1172/jci124099
Authors: Atsushi Yamamoto, Joanna Hester, Philip S. Macklin, Kento Kawai, Masateru Uchiyama, Daniel Biggs, Tammie Bishop, Katherine Bull, Xiaotong Cheng, Eleanor Cawthorne, Mathew L. Coleman, Tanya L. Crockford, Ben Davies, Lukas E. Dow, Rob Goldin, Kamil Kranc, Hiromi Kudo, Hannah Lawson, James McAuliffe, Kate Milward, Cheryl L. Scudamore, Elizabeth Soilleux, Fadi Issa, Peter J. Ratcliffe, Chris W. Pugh
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,412
Funders: U.S. Department of Veterans Affairs, GlaxoSmithKline, Memorial Sloan-Kettering Cancer Center, Queen Mary University of London, Ludwig Institute for Cancer Research, Wellcome Trust, Francis Crick Institute, Barts Charity, Universitätsspital Basel, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, Kidney Research UK, Academy of Medical Sciences, Imperial College London, University of Oxford, European Commission, Cardiff University, Jean Shanks Foundation, Medical Research Council, Oxford University Clinical Academic Graduate School
Awards: G1080657738, G1104134325, Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, G128354304, G1299486252, Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia, G1925698094, G2167674392, An investigation into the genetic and functional basis of proteinuric kidney disease, G2958185063, G3049251306, Personalized minimization of immunosuppression after solid organ transplantation by biomarker-driven stratification of patients to improve long-term outcome and health-economic data of transplantation, G3873106536, Defining a protein hydroxylase tumour suppressor pathway, Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia, G4885137792, G5102356368, G5114713889, Investigation of hypoxia-sensing mechanisms in immune regulation, Centre for cardiovascular drug target discovery, G5411179404, Defining the physiology and therapeutic potential of oxygenases as signalling enzymes., G5841612952, Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, G8435716022, G8538723892, G8801296868, G8871221442
OpenAlex ID: W2948752663