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CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons. JCI Insight 2022 Mar 22;7(6)

Date

03/23/2022

Pubmed ID

35315363

Pubmed Central ID

PMC8986072

DOI

10.1172/jci.insight.152186

Scopus ID

2-s2.0-85126883712 (requires institutional sign-in at Scopus site)   5 Citations

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.

Author List

Zhang X, Moore CM, Harmacek LD, Domenico J, Rangaraj VR, Ideozu JE, Knapp JR, Woods KJ, Jump S, Jia S, Prokop JW, Bowler R, Hessner MJ, Gelfand EW, Levy H

Authors

Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Katherine Woods in the CTSI department at Medical College of Wisconsin - CTSI




MESH terms used to index this publication - Major topics in bold

Cystic Fibrosis
Cystic Fibrosis Transmembrane Conductance Regulator
Humans
Leukocytes, Mononuclear
Macrophages
Monocytes
Parents