138 Dysregulation of epithelial miR-148b contributes to goblet cell metaplasia, inflammation and alveolar damage in cystic fibrosis lung disease

Abstract

Cystic fibrosis (CF) lung disease is primarily characterized by chronic mucus obstruction, inflammation and structural damage. While mutations in the CFTR gene are an initial trigger, molecular mechanisms underlying CF pathogenesis remains poorly understood. miRNAs are key regulators of diverse biological and pathological processes. Here, we identified association of miR-148b during the in vivo pathogenesis of CF using Scnn1b-overexpressing (Scnn1b-Tg) mice as a model of CF-like lung disease. miR-148b expression was elevated in the lung tissue of Scnn1b-Tg mice and is localized mainly in airway and alveolar epithelial cells. We demonstrate that ERBB receptor feedback inhibitor 1 (Errfi1) is one of the target genes of miR-148b. Antagomir-mediated selective silencing of miR-148b resulted in reduced goblet cell metaplasia, mucus hypersecretion, neutrophilic inflammation, and alveolar damage in the lungs of Scnn1b-Tg mice compared to wild-type. Our human studies demonstrate differential upregulation of miR-148b in the bronchial brushing of CF compared to non-CF individuals and localization in airway and alveolar epithelial cells. Further, we found that the allele distribution at MIR148B-Sat, a polymorphic marker that reflects the genetic variation at the human MIR148B gene, is associated with disease severity in F508del-CFTR homozygous sibling pairs. Together, this study provides a functional link between miR-148b and in vivo pathogenesis of CF and may have a potential for the development of novel therapeutic target.