Introduction: Epithelial cell-derived cytokines IL-25, IL-33 and TSLP initiate type 2 inflammation in allergic diseases. However, the signaling pathway regulating these cytokines expression remains elusive. We examined the role of epithelial microRNAs in the expression of IL-25, IL-33 and TSLP in asthma. Methods: Differentially expressed epithelial microRNAs between type 2-low and type 2-high asthma patients were identified using microarray. The expression of microRNA (miR)-206, its target CD39, CD39 substrate ATP, and IL-25, IL-33, TSLP were measured in epithelial brushings and bronchoalveolar lavage fluid from both asthma subsets and healthy controls. The links between these measurements were functionally validated in vitro and in vivo. Results: MiR-206 was the most highly expressed microRNA in type 2-high asthma relative to type 2-low asthma, but was downregulated in both asthma subsets compared with healthy controls. CD39, an ecto-nucleotidase degrading ATP, was a target of miR-206 and upregulated in asthma. Allergen-induced acute extracellular ATP accumulation led to miR-206 downregulation and CD39 upregulation in human bronchial epithelial cells, forming a feedback loop to eliminate excessive ATP. Airway ATP levels strongly correlated with elevated IL-25 and TSLP expression in type 2-high asthma patients. Intriguingly, airway miR-206 antagonism increased Cd39 expression, reduced ATP accumulation, suppressed Il-25, Il-33, Tslp expression and group 2 innate lymphoid cells expansion, and alleviated type 2 inflammation in a mouse model of asthma. However, airway miR-206 overexpression had opposite effects. Conclusion: Together, epithelial miR-206 upregulates airway IL-25, TSLP expression via targeting CD39-extracellular ATP axis, which represents a novel therapeutic target in type 2-high asthma.

中文翻译：

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通过靶向CD39-细胞外ATP轴，上皮微RNA上调2型高哮喘患者气道IL-25和TSLP表达

简介：上皮细胞衍生的细胞因子IL-25，IL-33和TSLP引发过敏性疾病中的2型炎症。但是，调节这些细胞因子表达的信号传导途径仍然难以捉摸。我们检查了哮喘中IL-25，IL-33和TSLP表达中上皮微小RNA的作用。方法：使用微阵列芯片识别2型低哮喘和2型高哮喘患者之间差异表达的上皮microRNA。在哮喘亚群和健康对照者的上皮刷洗和支气管肺泡灌洗液中测量了microRNA（miR）-206，其靶标CD39，CD39底物ATP和IL-25，IL-33，TSLP的表达。这些测量之间的联系已在体外和体内进行了功能验证。结果：相对于2型低度哮喘，MiR-206是2型高度哮喘中表达最高的microRNA，但与健康对照组相比，这两种哮喘亚型均被下调。CD39是一种可降解ATP的胞外核苷酸酶，是miR-206的靶标，在哮喘中表达上调。变应原诱导的急性细胞外ATP积累导致人支气管上皮细胞中miR-206下调和CD39上调，形成了一个消除过量ATP的反馈回路。在2型高哮喘患者中，气道ATP水平与IL-25和TSLP表达升高密切相关。有趣的是，在哮喘小鼠中，气道miR-206拮抗作用增加了Cd39的表达，减少了ATP的积累，抑制了Il-25，Il-33，Tslp的表达和第2组先天性淋巴样细胞的扩增，并减轻了2型炎症。但是，气道miR-206过表达具有相反的作用。结论：上皮miR-206共同上调气道IL-25，