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Opposing regulation and roles for PHD3 in lung dendritic cells and alveolar macrophages

(2017) JOURNAL OF LEUKOCYTE BIOLOGY. 102(4). p.1115-1126
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Abstract
The prolyl hydroxylase domain-containing enzymes (PHDs) are important metabolic sensors of the cell and its environment, which might be employed to alert cells of the immune system. These enzymes regulate the expression of the hypoxia inducible factor (HIF) isoforms and NF-kappa B, crucial transcription factors controlling cellular metabolism and inflammation. PHD/HIF signaling is activated in the allergic lung and is proposed as a potential druggable pathway. Here, we investigated the regulation and role of the PHD isoforms in CD11c-expressing dendritic cells (DCs) and macrophages (M phi), sensors of the environment and crucial antigen-presenting cells in the pathogenesis of asthma. Although PHD2 and PHD3 were expressed in baseline, stimulation with house dust mite (HDM) allergen, hypoxia, and TLR4 ligands induced the expression of PHD3 in DCs. Conditional deletion or overexpression of PHD3 in CD11c(hi) cells had minor effects on DCs and alveolar M phi biology in steady state. However, when put into competition with wild-type counterparts in mixed chimeric mice, alveolar M phi uniquely required PHD3 for optimal reconstitution of the alveolar space. Using genetic and chemical approaches, we were unable to find a clear role for PHD3 or the other PHD isoforms in DCs in asthma development. These data show cell-specific competitive advantage of PHD3 expression in antigen-presenting cells, but question whether therapeutic manipulation of PHDs in DCs would offer therapeutic benefit in asthma.
Keywords
HYPOXIA-INDUCIBLE FACTOR, HOUSE-DUST MITE, ALLERGIC AIRWAY INFLAMMATION, TISSUE-RESIDENT MACROPHAGES, HIF-ALPHA, EPITHELIAL-CELLS, FACTOR-I, T-CELLS, GM-CSF, HIF-1-ALPHA, HIF signaling, asthma, lung immunology, immune cell metabolism

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Chicago
Tavernier, Simon, Nele Vanlangenakker, Jessica Vetters, Peter Carmeliet, Sophie Janssens, and Bart Lambrecht. 2017. “Opposing Regulation and Roles for PHD3 in Lung Dendritic Cells and Alveolar Macrophages.” Journal of Leukocyte Biology 102 (4): 1115–1126.
APA
Tavernier, Simon, Vanlangenakker, N., Vetters, J., Carmeliet, P., Janssens, S., & Lambrecht, B. (2017). Opposing regulation and roles for PHD3 in lung dendritic cells and alveolar macrophages. JOURNAL OF LEUKOCYTE BIOLOGY, 102(4), 1115–1126.
Vancouver
1.
Tavernier S, Vanlangenakker N, Vetters J, Carmeliet P, Janssens S, Lambrecht B. Opposing regulation and roles for PHD3 in lung dendritic cells and alveolar macrophages. JOURNAL OF LEUKOCYTE BIOLOGY. 2017;102(4):1115–26.
MLA
Tavernier, Simon, Nele Vanlangenakker, Jessica Vetters, et al. “Opposing Regulation and Roles for PHD3 in Lung Dendritic Cells and Alveolar Macrophages.” JOURNAL OF LEUKOCYTE BIOLOGY 102.4 (2017): 1115–1126. Print.
@article{8556052,
  abstract     = {The prolyl hydroxylase domain-containing enzymes (PHDs) are important metabolic sensors of the cell and its environment, which might be employed to alert cells of the immune system. These enzymes regulate the expression of the hypoxia inducible factor (HIF) isoforms and NF-kappa B, crucial transcription factors controlling cellular metabolism and inflammation. PHD/HIF signaling is activated in the allergic lung and is proposed as a potential druggable pathway. Here, we investigated the regulation and role of the PHD isoforms in CD11c-expressing dendritic cells (DCs) and macrophages (M phi), sensors of the environment and crucial antigen-presenting cells in the pathogenesis of asthma. Although PHD2 and PHD3 were expressed in baseline, stimulation with house dust mite (HDM) allergen, hypoxia, and TLR4 ligands induced the expression of PHD3 in DCs. Conditional deletion or overexpression of PHD3 in CD11c(hi) cells had minor effects on DCs and alveolar M phi biology in steady state. However, when put into competition with wild-type counterparts in mixed chimeric mice, alveolar M phi uniquely required PHD3 for optimal reconstitution of the alveolar space. Using genetic and chemical approaches, we were unable to find a clear role for PHD3 or the other PHD isoforms in DCs in asthma development. These data show cell-specific competitive advantage of PHD3 expression in antigen-presenting cells, but question whether therapeutic manipulation of PHDs in DCs would offer therapeutic benefit in asthma.},
  author       = {Tavernier, Simon and Vanlangenakker, Nele and Vetters, Jessica and Carmeliet, Peter and Janssens, Sophie and Lambrecht, Bart},
  issn         = {0741-5400},
  journal      = {JOURNAL OF LEUKOCYTE BIOLOGY},
  language     = {eng},
  number       = {4},
  pages        = {1115--1126},
  title        = {Opposing regulation and roles for PHD3 in lung dendritic cells and alveolar macrophages},
  url          = {http://dx.doi.org/10.1189/jlb.3A0916-405R},
  volume       = {102},
  year         = {2017},
}

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