Gillan, Jonathan L.Chokshi, MithilHardisty, Gareth R.Clohisey Hendry, SaraPrasca-Chamorro, DanielRobinson, Nicola J.Lasota, BenjaminClark, RichardMurphy, LeeWhyte, Moira K. B.Baillie, J. KennethDavidson, Donald J.Bao, GangGray, Robert D.2023-07-212023-07-212023Gillan, Jonathan L., Chokshi, Mithil, Hardisty, Gareth R., et al.. "CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages." <i>Science Advances,</i> 9, no. 21 (2023) AAAS: https://doi.org/10.1126/sciadv.adg5128.https://hdl.handle.net/1911/115022An 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.engExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license.  Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of Fair Use or other exemptions to copyright law must be obtained from the copyright holder.Journal articlesciadv-adg5128https://doi.org/10.1126/sciadv.adg5128