Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have differential effects on cystic fibrosis...

Area of Science:

• Immunology
• Cell Biology
• Medical Science

Background:

• Cystic Fibrosis (CF) patients experience chronic infections and respiratory decline despite CFTR modulator therapies.
• Macrophage dysfunction is a key factor in CF patients' impaired ability to clear bacterial infections.
• The impact of CFTR modulators on macrophage function, varying by patient genotype, requires detailed characterization.

Purpose of the Study:

• To investigate the effects of CFTR modulators (ivacaftor, lumacaftor/ivacaftor) on macrophage function in cystic fibrosis.
• To compare macrophage responses in CF patients versus non-CF individuals following CFTR modulator treatment.
• To determine genotype-specific differences in macrophage responses to CFTR modulator therapy.

Main Methods:

• Human CF and non-CF peripheral blood monocyte-derived macrophages (MDMs) were utilized.
• Analysis included CFTR expression, apoptosis, polarization, phagocytosis, bacterial killing, and cytokine production.
• Microscopy, flow cytometry, and ELISA assays were employed for comprehensive assessment.

Main Results:

• CF MDMs exhibited lower CFTR expression, increased apoptosis, and reduced phagocytosis compared to non-CF MDMs.
• Ivacaftor therapy increased CFTR expression, decreased apoptosis, and enhanced phagocytosis.
• Ivacaftor normalized macrophage polarization, reduced Pseudomonas aeruginosa burden, and decreased inflammatory cytokine production.

Conclusions:

• CFTR modulators, particularly ivacaftor, demonstrate differential effects on macrophage function in cystic fibrosis.
• Ivacaftor treatment leads to improved macrophage-mediated bacterial killing and immune responses in CF patients.
• Lumacaftor/ivacaftor showed limited impact on macrophage function compared to ivacaftor alone.