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

Autor: Zhang X; Data Science program, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois, USA.; Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and., Moore CM; Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA., Harmacek LD; Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA., Domenico J; Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and., Rangaraj VR; Division of Pulmonary & Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA., Ideozu JE; Genomic Medicine, Genomics Research Center, AbbVie, North Chicago, Illinois, USA., Knapp JR; Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA., Woods KJ; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Jump S; Department of Pediatrics, National Jewish Health, Denver, Colorado, USA., Jia S; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.; Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA., Prokop JW; Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA., Bowler R; Division of Pulmonary and Critical Care Medicine, Department of Medicine, and., Hessner MJ; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.; Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA., Gelfand EW; Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.; Division of Immunology, Microbiology and Pediatrics, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA., Levy H; Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2022 Mar 22; Vol. 7 (6). Date of Electronic Publication: 2022 Mar 22.
DOI: 10.1172/jci.insight.152186
Abstrakt: 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.
Databáze: MEDLINE
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