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

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dc.citation.articleNumbereadg5128
dc.citation.issueNumber21
dc.citation.journalTitleScience Advances
dc.citation.volumeNumber9
dc.contributor.authorGillan, Jonathan L.
dc.contributor.authorChokshi, Mithil
dc.contributor.authorHardisty, Gareth R.
dc.contributor.authorClohisey Hendry, Sara
dc.contributor.authorPrasca-Chamorro, Daniel
dc.contributor.authorRobinson, Nicola J.
dc.contributor.authorLasota, Benjamin
dc.contributor.authorClark, Richard
dc.contributor.authorMurphy, Lee
dc.contributor.authorWhyte, Moira K. B.
dc.contributor.authorBaillie, J. Kenneth
dc.contributor.authorDavidson, Donald J.
dc.contributor.authorBao, Gang
dc.contributor.authorGray, Robert D.
dc.date.accessioned2023-07-21T16:14:10Z
dc.date.available2023-07-21T16:14:10Z
dc.date.issued2023
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.
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.
dc.identifier.digitalsciadv-adg5128
dc.identifier.doihttps://doi.org/10.1126/sciadv.adg5128
dc.identifier.urihttps://hdl.handle.net/1911/115022
dc.language.isoeng
dc.publisherAAAS
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.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleCAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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