Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma

Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway in...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2017-07, Vol.199 (1), p.48-61
Main Authors: Klaßen, Carina, Karabinskaya, Anna, Dejager, Lien, Vettorazzi, Sabine, Van Moorleghem, Justine, Lühder, Fred, Meijsing, Sebastiaan H, Tuckermann, Jan P, Bohnenberger, Hanibal, Libert, Claude, Reichardt, Holger M
Format: Article
Language:English
Subjects:
Animals
Asthma
Asthma - drug therapy
Asthma - immunology
Asthma - physiopathology
Dexamethasone
Dexamethasone - pharmacology
Dexamethasone - therapeutic use
Dimerization
Disease Models, Animal
Epithelial cells
Epithelial Cells - drug effects
Epithelial Cells - immunology
Epithelial Cells - metabolism
Gene expression
Gene Expression Regulation
Gene regulation
Glucocorticoids
Glucocorticoids - pharmacology
Glucocorticoids - therapeutic use
Inflammation - drug therapy
Inflammation - immunology
Mice
Mucous membrane
Receptors, Glucocorticoid - chemistry
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Respiratory Mucosa - drug effects
Respiratory Mucosa - immunology
Respiratory Mucosa - metabolism
Respiratory tract
Respiratory tract diseases
Signal Transduction
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Summary:Although glucocorticoids (GCs) are a mainstay in the clinical management of asthma, the target cells that mediate their therapeutic effects are unknown. Contrary to our expectation, we found that GC receptor (GR) expression in immune cells was dispensable for successful therapy of allergic airway inflammation (AAI) with dexamethasone. Instead, GC treatment was compromised in mice expressing a defective GR in the nonhematopoietic compartment or selectively lacking the GR in airway epithelial cells. Further, we found that an intact GR dimerization interface was a prerequisite for the suppression of AAI and airway hyperresponsiveness by GCs. Our observation that the ability of dexamethasone to modulate gene expression in airway epithelial cells coincided with its potency to resolve AAI supports a crucial role for transcriptional regulation by the GR in this cell type. Taken together, we identified an unknown mode of GC action in the treatment of allergic asthma that might help to develop more specific therapies in the future.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1601691