A New Target to Improve Airway Repair in Cystic Fibrosis
SUMMARY
Apicobasal polarity plays key roles in airway epithelial maturation and regeneration. Once polarized, the airway epithelium functions as a barrier against opportunistic pathogens. Yet, the mechanisms that temporally regulate polarization, a process which is disrupted in cystic fibrosis (CF), remain unclear. Here, the authors demonstrate the functional importance of connexin 43 (Cx43), a gap junction protein, which is normally repressed during regeneration of the airway epithelium. They show that prolonged post-transcriptional stabilization of Cx43 leads to altered collective cell orientation and compromised CF airway epithelial barrier. They report a bidirectional cooperation between Cx43 hemichannel function and adenosine signaling in disrupting ER-Golgi secretory axis, cytoskeleton dynamic and ectopic apical fibronectin production. Genetic and pharmacological inhibition of Cx43 channels re-established polarity and spatial organization of CF airway epithelial cells. Finally, targeting Cx43 hemichannels with mimetic peptides normalizes the CF-dependent fibronectin ectopic expression and prevents the enhanced Pseudomonas aeruginosa trapping to the CF epithelium. Their findings reveal a mechanism in which temporally controlled Cx43-mediated intercellular communication is crucial for coordinating intrinsic polarity programs and maintaining airway epithelium integrity.
Full article: https://doi.org/10.1038/s42003-026-10413-7
WHY IS THIS IMPORTANT?
Airway cells need a precise internal organisation called apicobasal polarity to form an effective barrier against infections. In cystic fibrosis (CF), this organisation is disrupted, making the lungs more vulnerable to bacteria such as Pseudomonas aeruginosa. This study identifies the protein connexin 43 (Cx43) as a key driver of this defect. When Cx43 remains abnormally active during airway repair, it disturbs cell-cell communication, the positioning of key cellular organelles, and polarized protein secretion. This leads to abnormal deposition of fibronectin on the airway surface, which promotes bacterial adhesion. Importantly, blocking Cx43 restores normal epithelial organisation and reduces bacterial binding. These findings are important because they reveal how defective intercellular communication affects epithelial repair in CF airways and suggest that targeting Cx43 could complement existing therapies to improve lung defence and reduce chronic infections.
Funding:
This work has been funded by Swiss National Science Foundation and the Cystic Fibrosis Switzerland Foundation.