CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages

Jonathan L Gillan, Mithil Chokshi, Gareth R Hardisty, Sara Clohisey Hendry, Daniel Prasca-Chamorro, Nicola J Robinson, Benjamin Lasota, Richard Clark, Lee Murphy, Moira K B Whyte, J Kenneth Baillie, Donald J Davidson, Gang Bao, Robert D Gray*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbereadg5128
Pages (from-to)1-17
Number of pages17
JournalScience Advances
Volume9
Issue number21
Early online date26 May 2023
DOIs
Publication statusPublished - 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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