CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Gillan, J L, Chokshi, M, Hardisty, G R, Clohisey Hendry, S, Prasca-Chamorro, D, Robinson, N J, Lasota, B, Clark, R, Murphy, L, Whyte, M K B, Baillie, J K, Davidson, D J, Bao, G & Gray, R D 2023, ' CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages ', Science Advances, vol. 9, no. 21, eadg5128, pp. 1-17 . https://doi.org/10.1126/sciadv.adg5128 |
| Popis: | 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: | OpenAIRE |
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