CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons
Xi Zhang, … , Erwin W. Gelfand, Hara Levy
Xi Zhang, … , Erwin W. Gelfand, Hara Levy
Published March 22, 2022
Citation Information: JCI Insight. 2022;7(6):e152186. https://doi.org/10.1172/jci.insight.152186.
View: Text | PDF
Research Article Pulmonology

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

Abstract

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, 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.

Authors

Xi Zhang, Camille M. Moore, Laura D. Harmacek, Joanne Domenico, Vittobai Rashika Rangaraj, Justin E. Ideozu, Jennifer R. Knapp, Katherine J. Woods, Stephanie Jump, Shuang Jia, Jeremy W. Prokop, Russell Bowler, Martin J. Hessner, Erwin W. Gelfand, Hara Levy

×

Figure 5

Compositions of monocytes and macrophages in the plasma and PBMC models are correlated with CF disease severity and progression.

Options: View larger image (or click on image) Download as PowerPoint
Compositions of monocytes and macrophages in the plasma and PBMC models ...
(A–E) Dot and box plots of cell composition scores (see Methods) of monocytes and macrophages in patients with CF grouped based on their (A and C) CFTR class, (B and D) pancreatic function, and (E) P. aeruginosa infection status. Estimations of cell numbers in each cell subset were compared between subgroups of patients with CF (F and G). Correlation analysis of cell abundance with sweat chloride and percent predicted FEV1. Plasma model (A, B, and E); PBMC model (C, D, F, and G). The means were compared by paired and unpaired independent t test, as appropriate; and P values were adjusted using Holm-Šidák method to control the family-wise error rate. The P value and R (correlation coefficient) were produced by a Pearson’s correlation analysis (normal distribution assumed). *P < 0.05, **P < 0.01. Mono, monocytes; Macro, macrophages; Macro_ac, activated macrophages; DC_ac, activated dendritic cells; PI, pancreatic insufficient; PS, pancreatic sufficient.