CFTR-mediated monocyte-macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR). Converging lines of evidence suggest that CF carriers with only one defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. Here, we performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control PBMCs or THP-1 cells incubated with the plasma of these subjects. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1{beta}, CXCL8, CREM) implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents and in the control innate immune cells incubated with proband or parent plasma. These data suggest that not only a homozygous but also a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the findings of lower numbers of circulating monocytes in CF probands and their parents compared to healthy controls, the abundance of mononuclear phagocyte subsets (macrophages, monocytes, and activated dendritic cells) which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.