microRNA‐218‐5p plays a protective role in eosinophilic airway inflammation via targeting δ‐catenin, a novel catenin in asthma

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 δ‐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.