Epidermal growth factor receptor signalling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease.
Epidermal growth factor receptor signalling regulates granulocyte-macrophage colony-stimulating factor production by airway epithelial cells and established allergic airway disease.
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表皮生长因子受体信号传导调节气道上皮细胞产生的粒细胞巨噬细胞群刺激因子并建立过敏性气道疾病。
DOI：
10.1111/cea.12612
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Le Cras TD
中科院分区：
文献类型：
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作者：
Acciani TH;Suzuki T;Trapnell BC;Le Cras TD
气道上皮细胞（AEC）越来越被认为是过敏性哮喘发病机制的主要信号中心。先前的一项研究表明，AEC中的上皮生长因子受体（EGFR）信号传导调节变应性气道疾病的关键特征。然而，尽管促炎细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）的产生在角化细胞中依赖于EGFR，但尚不清楚AEC中哪些介质受EGFR信号的调节。在小鼠过敏性哮喘模型中，确定EGFR信号是否通过临床相关介质屋尘螨（HDM）和白细胞介素(IL)-17A下游的人AEC调节GM-CSF的产生。使用EGFR抑制剂来确定EGFR信号是否调节培养的人AEC对HDM和IL-17A的GM-CSF产生。还评估了EGFR配体、p38丝裂原活化蛋白激酶（MAPK）和肿瘤坏死因子α (TNFα)转换酶（TACE）的作用。为了确定EGFR是否调节GM-CSF以及体内哮喘的关键特征，将小鼠长期暴露于HDM以建立过敏性气道疾病，然后用EGFR抑制剂厄洛替尼治疗。在培养的人AEC中，EGFR抑制以剂量依赖的方式减少HDM和IL-17A诱导的GM-CSF产生。GM-CSF的生产还需要双调节蛋白、p38 MAPK信号和蛋白酶/TACE活性。在患有变应性气道疾病的小鼠中，EGFR抑制降低了GM-CSF和TNFα的水平，以及气道高反应性、细胞炎症、平滑肌增厚和杯状细胞化生，而IgE和Th1、Th2和Th17细胞因子没有变化。结果表明，在AEC中，HDM、IL-17A、双调节蛋白、EGFR和GM-CSF存在一条机制通路，并在临床相关哮喘模型中证实EGFR调节GM-CSF的产生和既定疾病的严重程度。这些结果确定EGFR→GM-CSF轴是治疗发展的靶点。
Airway epithelial cells (AEC) are increasingly recognized as a major signaling center in the pathogenesis of allergic asthma. A previous study demonstrated that epithelial growth factor receptor (EGFR) signaling in AEC regulated key features of allergic airway disease. However, it is unclear what mediators are regulated by EGFR signaling in AEC, although the production of the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is EGFR-dependent in keratinocytes. To determine if EGFR signaling regulates GM-CSF production by human AEC downstream of the clinically relevant mediators house dust mite (HDM) and interleukin (IL)-17A and in a mouse model of established allergic asthma. EGFR inhibitors were used to determine whether EGFR signaling regulates GM-CSF production by cultured human AEC in response to HDM and IL-17A. The roles of EGFR ligands, p38 mitogen activated protein kinase (MAPK), and tumor necrosis factor alpha (TNFα) converting enzyme (TACE) were also assessed. To determine if EGFR regulates GM-CSF as well as key asthma characteristics in vivo, mice were chronically exposed to HDM to establish allergic airway disease and then treated with the EGFR inhibitor Erlotinib. EGFR inhibition reduced HDM and IL-17A induced GM-CSF production in a dose-dependent manner in cultured human AEC. GM-CSF production also required amphiregulin, p38 MAPK signaling, and protease/TACE activity. In mice with established allergic airway disease, EGFR inhibition reduced levels of GM-CSF and TNFα, as well as airway hyperreactivity, cellular inflammation, smooth muscle thickening, and goblet cell metaplasia without changes in IgE and Th1, Th2, and Th17 cytokines. Results link HDM, IL-17A, amphiregulin, EGFR and GM-CSF in a mechanistic pathway in AEC, and demonstrate that EGFR regulates GM-CSF production and the severity of established disease in a clinically relevant asthma model. These results identify the EGFR→GM-CSF axis as a target for therapeutic development.