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

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Figure 8

Integrated pathway enrichment analysis suggests an LPS-tolerant state in CF trios.

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Integrated pathway enrichment analysis suggests an LPS-tolerant state in...
(A) Bubble plot of the top 5 significant upstream regulators and causal networks, ranked by P value, from Ingenuity Pathway Analysis (IPA) using genetic profiles from the PBMC model (see Methods). (B) Flow of identification and selection to identify input gene set 1 for gene set enrichment analysis (GSEA). First, the overlapping coding genes (n = 157) from the PBMC and plasma models (CF proband versus HC) were identified. Then, the overlapping genes (n = 140) from these genes with DEGs from comparison of CF participants versus HCs were identified; the final input gene set (n = 138) were identified as the genes regulated in same directions in both PBMC and plasma models. P, proband; F, father; M, mother. (C) Bubble plot of gene sets from GSEA matched with input gene set 1. The top 10 matched gene sets were ranked by q value (FDR). (D) Left, Venn diagram of the 22 overlapping genes from input gene set 1 and the annotated LPS-inducible gene set (GSE9988). Right, bar plot of fold change (log2) of the expression levels of genes in both input gene set 1 and the annotated LPS-inducible gene set (CF or LPS versus HC). Fold change values from input gene set 1 were reversed from negative to positive for ease of visualization. The P value and R2 (square of the correlation coefficient) were produced by a Pearson’s correlation analysis.