Projects per year
Abstract
An intense, nonresolving airway inflammatory response leads to destructive lung disease in cystic fibrosis (CF). Dysregulation of macrophage immune function may be a key facet governing the progression of CF lung disease, but the underlying mechanisms are not fully understood. We used 5' end centered transcriptome sequencing to profile P. aeruginosa LPS-activated human CF macrophages, showing that CF and non-CF macrophages deploy substantially distinct transcriptional programs at baseline and following activation. This includes a significantly blunted type I IFN signaling response in activated patient cells relative to healthy controls that was reversible upon in vitro treatment with CFTR modulators in patient cells and by CRISPR-Cas9 gene editing to correct the F508del mutation in patient-derived iPSC macrophages. These findings illustrate a previously unidentified immune defect in human CF macrophages that is CFTR dependent and reversible with CFTR modulators, thus providing new avenues in the search for effective anti-inflammatory interventions in CF.
Original language | English |
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Article number | eadg5128 |
Pages (from-to) | 1-17 |
Number of pages | 17 |
Journal | Science Advances |
Volume | 9 |
Issue number | 21 |
Early online date | 26 May 2023 |
DOIs | |
Publication status | Published - 26 May 2023 |
Keywords / Materials (for Non-textual outputs)
- Humans
- Cystic Fibrosis/genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Macrophages/metabolism
- Signal Transduction
- Mutation
- Pseudomonas aeruginosa
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Dive into the research topics of 'CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages'. Together they form a unique fingerprint.Projects
- 2 Active
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The basis of natural and vaccine-mediated immunity
Wilson, A. (Principal Investigator)
1/04/23 → 31/03/28
Project: Research
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Equipment
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Genetics Core, Edinburgh Clinical Research Facility
Murphy, L. (Manager), Fawkes, A. (Other), Hafezi, K. (Other), Clark, R. (Other), MacCallum, A. (Other), Aitken, E. (Other) & Macgillivray, L. (Other)
Deanery of Clinical SciencesFacility/equipment: Facility
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Institute for Regeneration and Repair Flow Cytometry Facility
Johnston, S. (Manager), Rossi, F. (Manager), Cryer, C. (Other) & Laird, A. (Other)
Institute of Regeneration and RepairFacility/equipment: Facility