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Scientific article
English

Akt-driven TGF-β and DKK1 Secretion Impairs F508del CF Airway Epithelium Polarity

Publication date2024-03-26
First online date2024-03-26
Abstract

Epithelial polarity is fundamental in maintaining barrier integrity and tissue protection. In cystic fibrosis (CF), apicobasal polarity of the airway epithelium is altered, resulting in increased apical fibronectin deposition and enhanced susceptibility to bacterial infections. Here, we evaluated the effect of highly effective modulator treatment (HEMT) on fibronectin apical deposition and investigated the intracellular mechanisms triggering the defect in polarity of the CF airway epithelium. To this end, primary cultures of CF (F508del variant) human airway epithelial cells (HAECs) and a HAEC line, Calu-3, knocked-down (KD) forCFTR(CFTR KD) were compared to control counterparts, grown at an air-liquid interface (ALI). We show thatCFTRmutation in primary HAECs andCFTRKD cells promote the overexpression and over-secretion of TGF-β1 and DKK1 when cultured at ALI. These dynamic changes result in hyperactivation of the TGF-β pathway and inhibition of the Wnt pathway through degradation of β-catenin leading to imbalanced proliferation and polarization. The abnormal interplay between TGF-β and Wnt signaling pathways is reinforced by aberrant Akt signaling. Pharmacological manipulation of TGF-β, Wnt, and Akt pathways restored polarization of the F508del CF epithelium, a correction that was not achieved by HEMT. Our data shed new insights into the signaling pathways that fine-tune apicobasal polarization in primary airway epithelial cells and may provide an explanation to the mitigated efficacy of HEMT on lung infection in people with CF.

eng
Keywords
  • Akt
  • CFTR modulators
  • DKK1
  • Polarity
  • TGF-β
Citation (ISO format)
IDRIS, Tahir et al. Akt-driven TGF-β and DKK1 Secretion Impairs F508del CF Airway Epithelium Polarity. In: American journal of respiratory cell and molecular biology, 2024. doi: 10.1165/rcmb.2023-0408OC
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Article (Accepted version)
accessLevelRestrictedaccessLevelPublic 03/27/2025
Identifiers
ISSN of the journal1044-1549
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