Akt Drives TGF-beta-induced Over-secretion of DKK1 and Impairment of Cystic Fibrosis Airway Epithelium Polarity

Abstract

Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is lost, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here we show that CFTR mutation in primary human airway epithelial cells (HAECs) and CFTR knockdown in a HAEC line promote the overexpression and over-secretion of TGF-{beta}1 and DKK1 when cultured at air-liquid interface (ALI). These dynamic changes result in hyperactivation of the TGF-{beta} pathway and inhibition of the Wnt pathway through degradation of {beta}-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-{beta} and Wnt signaling pathways is further enhanced by aberrant Akt signaling. Pharmacological manipulation of TGF-{beta}, Wnt, and Akt pathways restored polarization of the CF epithelium. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization and also highlight new therapeutic strategies in preventing infections in CF HAECs.