Systemic silencing of PHD2 causes reversible immune regulatory dysfunction
| Autor: | Yamamoto, A, Hester, J, Macklin, PS, Kawai, K, Uchiyama, M, Biggs, D, Bishop, T, Bull, K, Cheng, X, Cawthorne, E, Coleman, ML, Crockford, TL, Davies, B, Dow, LE, Goldin, R, Kranc, K, Kudo, H, Lawson, H, McAuliffe, J, Milward, K, Scudamore, CL, Soilleux, E, Issa, F, Ratcliffe, PJ, Pugh, CW |
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| Přispěvatelé: | Soilleux, Elizabeth [0000-0002-4032-7249], Apollo - University of Cambridge Repository |
| Rok vydání: | 2019 |
| Předmět: |
HOMEOSTASIS
Autoimmune diseases Immunology PROLYL HYDROXYLASES PROTEIN Mice Transgenic Therapeutics Research & Experimental Medicine Mouse models T-Lymphocytes Regulatory Hypoxia-Inducible Factor-Proline Dioxygenases Mice Basic Helix-Loop-Helix Transcription Factors Animals HYPOXIA-INDUCIBLE FACTOR-1-ALPHA 11 Medical and Health Sciences Science & Technology STABILITY hypoxia DIFFERENTIATION Medicine Research & Experimental HYDRALAZINE T-CELLS RNA Interference ERYTHROPOIESIS Life Sciences & Biomedicine RESPONSES Signal Transduction |
| Zdroj: | Journal of Clinical Investigation. 129(9) |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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