An epithelial microRNA upregulates airway IL-25 and TSLP expression in type 2-high asthma via targeting CD39-extracellular ATP axis

The presence of type 2 inflammation is a prominent endotype of asthma. Airway epithelial cell-derived cytokines IL-25, IL-33 and TSLP initiate type 2 inflammation. However, the upstream signaling pathway regulating these cytokines’ expression remains elusive. We identified a small set of epithelial microRNAs differentially expressed between type 2-low and –high asthma patients. 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 to control subjects. CD39, an ecto-nucleotidase degrading extracellular ATP, was a target of miR-206 and upregulated in asthma. In cultured human bronchial epithelial cells, allergen-induced rapid accumulation of extracellular ATP was responsible for miR-206 downregulation and CD39 upregulation, suggesting a protective mechanism to eliminate excessive ATP. Importantly, BALF ATP levels were increased in asthma patients, and strongly correlated with elevated IL-25 and TSLP expression in type 2-high asthma. Intriguingly, inhibition of airway miR-206 increased Cd39 expression, suppressed airway ATP accumulation and Il-25, Il-33, Tslp expression, and alleviated type 2 inflammation in a mouse model of asthma. In contrast, airway miR-206 overexpression had opposite effects. Taken together, airway epithelial miR-206 upregulates IL-25, TSLP expression via targeting CD39-extracellular ATP axis in type 2-high asthma.