Differential bronchial epithelial response regulated by ΔNp63: a functional understanding of the epithelial shedding found in asthma
Differential bronchial epithelial response regulated by ΔNp63: a functional understanding of the epithelial shedding found in asthma
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DOI：
10.1038/s41374-018-0132-6
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发表时间：
2019-02-01
影响因子：
5
通讯作者：
Torigoe, Toshihiko
中科院分区：
文献类型：
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作者：
Kubo, Terufumi;Tsujiwaki, Mitsuhiro;Torigoe, Toshihiko
支气管上皮细胞在免疫系统的前沿充当物理屏障。屏障破坏和支气管上皮过度的免疫反应有助于哮喘的病理生理，慢性支气管炎症性疾病。本研究的目的是探讨Delta Np63的功能意义，Delta Np63是一种由基底支气管上皮表达的p53样转录因子。在哮喘患者支气管组织中评估Delta Np63的免疫组织化学表达谱。利用体外培养的BEAS-2B支气管上皮细胞，采用分子生物学方法研究了Delta Np63在细胞凋亡抑制和可溶性介质产生中的作用。在健康支气管组织中，Delta np63阳性的基底上皮细胞被分化的Delta np63阴性细胞覆盖，但在哮喘气道中，由于严重的上皮脱落，Delta np63阳性细胞直接暴露于支气管腔内。Np63在toll样受体3刺激下调控支气管细胞凋亡。另一方面，Delta Np63的表达可通过胰蛋白酶和SLIGKV（蛋白酶激活受体2配体）的刺激来调节。进一步的表型分析显示，Delta Np63控制了一些上皮源性促炎细胞因子和内源性蛋白酶抑制剂的转录表达和蛋白质释放。我们得出结论，Delta Np63调节支气管上皮对病毒感染的反应。同时，Delta Np63的表达受蛋白酶的影响，而这些蛋白酶在室内尘螨中含量丰富。因此，Delta Np63轴将密切参与哮喘恶化的这两个主要触发因素，病毒感染和蛋白酶超载。
Bronchial epithelial cells serve as a physical barrier at the forefront of the immune system. Barrier disruption and an excessive immune response of the bronchial epithelium contribute to the pathophysiology of asthma, a chronic bronchial inflammatory disease. The purpose of this study was to investigate the functional significance of Delta Np63, a p53-like transcription factor expressed by the basal bronchial epithelium. The immunohistochemical expression profile of Delta Np63 was evaluated in human bronchial tissue derived from asthma patients. The role of Delta Np63 in apoptosis inhibition and production of soluble mediators was investigated in vitro with cultured BEAS-2B bronchial epithelial cells using molecular biological analysis. In healthy bronchial tissue,Delta Np63-positive basal epithelial cells were covered with differentiated Delta Np63-negative cells but in the asthmatic airway,Delta Np63-positive cells were directly exposed to the bronchial lumen due to severe epithelial shedding. Delta Np63 regulated bronchial apoptosis in response to Toll-like receptor 3 stimulation. On the other hand, expression of Delta Np63 was modulated by stimulation with trypsin and SLIGKV, protease-activated receptor 2 ligands. Further phenotypic analysis revealed that Delta Np63 controlled the transcriptional expression and protein release of some epithelium-derived proinflammatory cytokines and endogenous protease inhibitors. We conclude that Delta Np63 modulates the bronchial epithelial response to viral infection. At the same time, Delta Np63 expression is influenced by proteases, which are abundant in house dust mites. Therefore, the Delta Np63 axis would be intimately involved in these two major triggers of asthma exacerbations, viral infection and protease overload.