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

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dc.citation.articleNumbereadg5128en_US
dc.citation.issueNumber21en_US
dc.citation.journalTitleScience Advancesen_US
dc.citation.volumeNumber9en_US
dc.contributor.authorGillan, Jonathan L.en_US
dc.contributor.authorChokshi, Mithilen_US
dc.contributor.authorHardisty, Gareth R.en_US
dc.contributor.authorClohisey Hendry, Saraen_US
dc.contributor.authorPrasca-Chamorro, Danielen_US
dc.contributor.authorRobinson, Nicola J.en_US
dc.contributor.authorLasota, Benjaminen_US
dc.contributor.authorClark, Richarden_US
dc.contributor.authorMurphy, Leeen_US
dc.contributor.authorWhyte, Moira K. B.en_US
dc.contributor.authorBaillie, J. Kennethen_US
dc.contributor.authorDavidson, Donald J.en_US
dc.contributor.authorBao, Gangen_US
dc.contributor.authorGray, Robert D.en_US
dc.date.accessioned2023-07-21T16:14:10Zen_US
dc.date.available2023-07-21T16:14:10Zen_US
dc.date.issued2023en_US
dc.description.abstractAn 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.en_US
dc.identifier.citationGillan, 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.en_US
dc.identifier.digitalsciadv-adg5128en_US
dc.identifier.doihttps://doi.org/10.1126/sciadv.adg5128en_US
dc.identifier.urihttps://hdl.handle.net/1911/115022en_US
dc.language.isoengen_US
dc.publisherAAASen_US
dc.rightsExcept 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleCAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophagesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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