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Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia

Dana C Borcherding1, Matthew E Siefert1, Songbai Lin1,2

  • 1Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

The Journal of Clinical Investigation
|May 31, 2019
PubMed

Insights

Cystic Fibrosis (CF) drug VX809/VX661 restores nuclear-factor-E2-related factor-2 (Nrf2) function in CF cells. This correction is linked to improved cystic fibrosis transmembrane conductance regulator (CFTR) function, highlighting a new therapeutic target.

Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Medicine

Background:

  • Cystic Fibrosis (CF) is a genetic disorder caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein.
  • Nuclear-factor-E2-related factor-2 (Nrf2), a key regulator of cellular defense mechanisms, is impaired in CF.

Purpose of the Study:

  • To investigate if CFTR correctors can restore Nrf2 function in CF.
  • To elucidate the mechanism by which CFTR correctors impact Nrf2 activity.

Main Methods:

  • Proximity ligation assay, immunoprecipitation, and immunofluorescence were used to assess Nrf2 and CFTR colocalization.
  • Nrf2-dependent reporter gene assays and target gene expression analysis were performed.
  • Experiments involved primary human bronchial epithelial cells from CF patients and CFTR knockdown models.

Main Results:

  • CFTR correctors VX809/VX661 restored Nrf2 function and its colocalization with CFTR in CF cells.
  • These correctors promoted Nrf2 nuclear translocation and transcriptional activity.
  • Nrf2 rescue was dependent on CFTR correction and functional channel activity.

Conclusions:

  • Modulation of F508del-CFTR function by approved correctors can restore Nrf2 dysfunction in Cystic Fibrosis.
  • This suggests a direct link between CFTR function and redox/inflammatory signaling pathways regulated by Nrf2.
Keywords:
Chloride channelsGenetic diseasesPulmonology

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