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

Autor: Gillan JL; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK., Chokshi M; Department of Bioengineering, Rice University, Houston, TX, USA., Hardisty GR; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK., Clohisey Hendry S; The Roslin Institute, University of Edinburgh, Edinburgh, EH25 9RG., Prasca-Chamorro D; Department of Bioengineering, Rice University, Houston, TX, USA., Robinson NJ; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK., Lasota B; Department of Bioengineering, Rice University, Houston, TX, USA., Clark R; Edinburgh Clinical Research Facility, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK., Murphy L; Edinburgh Clinical Research Facility, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK., Whyte MKB; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK., Baillie JK; The Roslin Institute, University of Edinburgh, Edinburgh, EH25 9RG., Davidson DJ; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK., Bao G; Department of Bioengineering, Rice University, Houston, TX, USA., Gray RD; University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2023 May 26; Vol. 9 (21), pp. eadg5128. Date of Electronic Publication: 2023 May 26.
DOI: 10.1126/sciadv.adg5128
Abstrakt: 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.
Databáze: MEDLINE