ArticleThe Journal of clinical investigation2019
Systemic silencing of PHD2 causes reversible immune regulatory dysfunction.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia.Nature reviews. Immunology · 2025Review
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.Nature cancer · 2024Article
- Immunoregulation: the interplay between metabolism and redox homeostasis.Frontiers in transplantation · 2023Review
- Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease.Frontiers in pharmacology · 2023Review
- Article
- Harveian Oration 2020: Elucidation of molecular oxygen sensing mechanisms in human cells: implications for medicine.Clinical medicine (London, England) · 2022Article
- EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells.Nature communications · 2021Article
- Precisely Tuned Inhibition of HIF Prolyl Hydroxylases Is Key for Cardioprotection After Ischemia.Circulation research · 2021Article
- HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer-Potential Targets for Anti-Tumor Therapy?Cancers · 2021Review
- Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment.Frontiers in immunology · 2021Review
- The Endoplasmic Reticulum Cargo Receptor SURF4 Facilitates Efficient Erythropoietin Secretion.Molecular and cellular biology · 2020Article
- Hypoxia-inducible factor signaling in pulmonary hypertension.The Journal of clinical investigation · 2020Review
- Hypoxic Melanoma Cells Deliver microRNAs to Dendritic Cells and Cytotoxic T Lymphocytes through Connexin-43 Channels.International journal of molecular sciences · 2020Article
- Metabolic factors contribute to T-cell inhibition in the ovarian cancer ascites.International journal of cancer · 2020Review
- An injectable hydrogel-formulated inhibitor of prolyl-4-hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1.Journal of the American Society of Nephrology : JASN · 2020Article
- Label-Free Interactome Analysis Revealed an Essential Role of CUL3-KEAP1 Complex in Mediating the Ubiquitination and Degradation of PHD2.Journal of proteome research · 2020Article
- Mechanisms of hypoxia signalling: new implications for nephrology.Nature reviews. Nephrology · 2019Review
- A PHD in immunosuppression: oxygen-sensing pathways regulate immunosuppressive Tregs.The Journal of clinical investigation · 2019Article
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25 authors at 9 institutions in 3 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.