Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma
Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma
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DOI：
10.4049/jimmunol.1601691
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发表时间：
2017-07-01
影响因子：
4.4
通讯作者：
Reichardt, Holger M.
中科院分区：
文献类型：
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作者：
Klassen, Carina;Karabinskaya, Anna;Reichardt, Holger M.
尽管糖皮质激素（GC）是哮喘临床治疗的主要药物，但介导其治疗效果的靶细胞尚不清楚。与我们的预期相反，我们发现免疫细胞中GC受体（GR）的表达与地塞米松治疗过敏性气道炎症（AAI）的成功无关。相反，GC治疗在非造血区室中表达有缺陷的GR或在气道上皮细胞中选择性缺乏GR的小鼠中受到损害。此外，我们发现完整的GR二聚化界面是GC抑制AAI和气道高反应性的先决条件。我们观察到地塞米松调节气道上皮细胞中基因表达的能力与其解决AAI的效力相一致，这支持GR在这种细胞类型中的转录调节的关键作用。综上所述，我们确定了一种未知的GC治疗过敏性哮喘的作用模式，这可能有助于将来开发更特异的治疗方法。
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.