Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in chronic bacterial lung infections and tissue damage. CF macrophages exhibit reduced bacterial killing and increased inflammatory signaling. Iron is elevated in the CF lung and is a critical nutrient for bacteria, including the common CF pathogen Pseudomonas aeruginosa (Pa). While macrophages are a key regulatory component of extracellular iron, iron metabolism has yet to be characterized in human CF macrophages. Secreted and total protein levels were analyzed in non-CF and F508del/F508del CF monocyte derived macrophages (MDMs) with and without clinically approved CFTR modulators ivacaftor/lumacaftor. CF macrophage transferrin receptor 1 (TfR1) was reduced with ivacaftor/lumacaftor treatment. When activated with LPS, CF macrophage expressed reduced ferroportin (Fpn). After the addition of exogenous iron, total iron was elevated in conditioned media from CF MDMs and reduced in conditioned media from ivacaftor/lumacaftor treated CF MDMs. Pa biofilm formation and viability were elevated in conditioned media from CF MDMs and biofilm formation was reduced in the presence of conditioned media from ivacaftor/lumacaftor treated CF MDMs. Defects in iron metabolism observed in this study may inform host–pathogen interactions between CF macrophages and Pa.
Highlights
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in chronic bacterial lung infections and tissue damage
Regardless of ex vivo modulator pretreatment, we found that prescribed modulator use in vivo coincided with a trend in lower hepcidin secretion in LPS-activated CF monocyte derived macrophages (MDMs) compared to LPS-activated CF MDMs from patients who did not use in vivo modulators (Supplementary Fig. S3e)
As manipulation of iron availability has become a therapeutic option of interest for CF lung infections[60,61,62], expanding our understanding of iron metabolism in primary CF macrophages could offer insight into airway host–pathogen interactions
Summary
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in chronic bacterial lung infections and tissue damage. Increased mucin content is associated with neutrophil recruitment and inflammatory markers in the bronchoalveolar lavage of young children with C F4 and CFTR knockout ferrets[5] These changes in airway pH, bacterial clearance, and inflammatory milieu facilitate chronic lung disease and bacterial infection over the lifetime of the CF patient[6]. In addition to being integral phagocytic first responders to airway pathogens such as Pa, lung macrophages regulate and coordinate the inflammatory milieu and neutrophil r ecruitment[20]. Both extrinsic (pulmonary microenvironment) and intrinsic (CFTR expression) factors inform the CF macrophage immunophenotype[21,22,23]. CFTR dysfunction perturbs mitochondrial activity, anti-bacterial metabolite production, and reactive oxygen species (ROS) g eneration[28,29], demonstrating broad implications for CF macrophage dysfunction
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