microRNA-218-5p plays a protective role in eosinophilic airway inflammation via targeting δ-catenin, a novel catenin in asthma
microRNA-218-5p plays a protective role in eosinophilic airway inflammation via targeting δ-catenin, a novel catenin in asthma
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microRNA-218-5p 通过靶向 δ-连环蛋白（一种哮喘中的新型连环蛋白）在嗜酸性粒细胞气道炎症中发挥保护作用
DOI：
10.1111/cea.13498
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发表时间：
2019-10-06
影响因子：
6.1
通讯作者：
Zhen, Guohua
中科院分区：
文献类型：
--
作者：
Liang, Yuxia;Feng, Yuchen;Zhen, Guohua
microRNA (miR)-218-5p参与香烟烟雾诱导的气道炎症。在我们早期的哮喘上皮miRNA分析数据中，miR-218-5p是下调最多的2个miRNA。我们假设miR-218-5p在哮喘气道炎症中发挥作用。目的探讨miR-218-5p及其靶基因在哮喘气道炎症中的作用。方法测定哮喘患者（n = 50）和健康对照（n = 15）支气管刷毛中miR-218-5p的表达，分析miR-218-5p表达与气道嗜酸性粒细胞增多的相关性。我们检测了CTNND2是否是miR-218-5p的靶点，以及12个catenin家族成员在支气管刷、培养的人支气管上皮细胞（HBE）和BEAS-2B细胞中的表达。我们通过小鼠变应性气道炎症模型探讨了miR-218-5p-CTNND2通路的作用。结果哮喘患者上皮组织miR-218-5p表达显著降低，并与诱导痰和支气管活检中的嗜酸性粒细胞及其他2型生物标志物呈负相关。我们证实CTNND2（编码delta-catenin）是miR-218-5p的靶标。值得注意的是，在哮喘患者的支气管刷、il -13刺激的HBE和BEAS-2B细胞中，与其他11个catenin家族成员相比，CTNND2是上调最显著的catenin。此外，上皮细胞CTNND2的表达与哮喘患者气道嗜酸性粒细胞增多呈正相关。在小鼠变应性气道炎症模型中，气道mum - mir -218-5p表达也降低，Ctnnd2表达升高。有趣的是，在小鼠模型中，mmu-miR-218-5p过表达抑制气道高反应性、嗜酸性气道炎症和Ctnnd2上调。最后，干扰miR-218-5p或CTNND2表达可显著改变细胞培养和小鼠模型中趋化因子CCL26的表达。上皮细胞miR-218-5p通过靶向哮喘中的一种新型连环蛋白CTNND2并抑制趋化因子CCL26的表达，在嗜酸性气道炎症中发挥保护作用。
Background microRNA (miR)-218-5p is involved in cigarette smoke-induced airway inflammation. In our earlier asthma epithelial miRNA profiling data, miR-218-5p was the top 2 down-regulated miRNA. We hypothesize that miR-218-5p plays a role in asthma airway inflammation. Objective To unveil the role of miR-218-5p and its target gene in asthma airway inflammation. Methods We measured miR-218-5p expression in bronchial brushings of asthma patients (n = 50) and healthy controls (n = 15), and analysed the correlations between miR-218-5p expression and airway eosinophilia. We examined whether CTNND2 was a target of miR-218-5p, and the expression of 12 catenin family members in bronchial brushings, in cultured human bronchial epithelial (HBE) cells and BEAS-2B cells. We explored the role of miR-218-5p-CTNND2 pathway using a murine model of allergic airway inflammation. Results Epithelial miR-218-5p expression was significantly decreased and negatively correlated with eosinophils in induced sputum and bronchial biopsies, and other type 2 biomarkers in asthma patients. We verified that CTNND2 (encoding delta-catenin) was a target of miR-218-5p. Remarkably, CTNND2 was the most significantly up-regulated catenin compared with the other 11 catenin family members in bronchial brushings of asthma patients, IL-13-stimulated HBE and BEAS-2B cells. Moreover, epithelial CTNND2 expression positively correlated with airway eosinophilia in asthma. Airway mmu-miR-218-5p expression was also decreased, and Ctnnd2 expression was increased in a murine model of allergic airway inflammation. Intriguingly, mmu-miR-218-5p overexpression suppressed airway hyperresponsiveness, eosinophilic airway inflammation and Ctnnd2 up-regulation in the mouse model. Finally, perturbation of miR-218-5p or CTNND2 expression significantly altered chemokine CCL26 expression in the cell cultures and the mouse model. Conclusions and Clinical Relevance Epithelial miR-218-5p plays a protective role in eosinophilic airway inflammation via targeting CTNND2, a novel catenin in asthma, and suppressing chemokine CCL26 expression.