Abstract / Description of output
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.
Keywords / Materials (for Non-textual outputs)
- Cystic Fibrosis/genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Signal Transduction
- Pseudomonas aeruginosa
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Shonna Johnston (Manager), Fiona Rossi (Manager), Claire Cryer (Other) & Ailsa Laird (Other)Institute of Regeneration and Repair