Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation

Area of Science:

• Immunology
• Pulmonology
• Hematology

Background:

• Cystic fibrosis (CF) lung disease involves significant inflammation, potentially leading to respiratory failure.
• The cystic fibrosis transmembrane conductance regulator (CFTR) protein is crucial for regulating cellular functions, and its mutation is central to CF pathogenesis.
• Platelets, known participants in immune responses, may play an underappreciated role in CF-related inflammation.

Purpose of the Study:

• To investigate the role of CFTR in platelet function and its contribution to lung inflammation in cystic fibrosis.
• To explore the potential of targeting platelet CFTR and associated channels for therapeutic benefit in CF lung disease.

Main Methods:

• Deletion of CFTR in mouse platelets to assess lung inflammation and platelet activation.
• Analysis of platelet activation, calcium influx, and lung injury in response to LPS and Pseudomonas aeruginosa challenge.
• Assessment of CFTR function in human platelets from CF subjects receiving CFTR modulator therapy.
• Inhibition of the transient receptor potential cation channel 6 (TRPC6) to evaluate its impact on platelet activation and lung injury.

Main Results:

• CFTR deletion in platelets exacerbated acute lung inflammation and platelet activation.
• Loss of CFTR function in platelets led to hyperactivation and increased calcium entry.
• TRPC6 inhibition reduced platelet activation, calcium flux, and lung injury in CF models.
• CFTR modulator therapy partially restored CFTR function in platelets of CF subjects.

Conclusions:

• CFTR dysfunction in platelets promotes aberrant, TRPC6-dependent platelet activation, a key driver of CF lung inflammation.
• Dysfunctional platelets contribute significantly to impaired bacterial clearance in cystic fibrosis.
• Platelets and TRPC6 represent promising novel therapeutic targets for managing CF lung disease.