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CAGE sequencing reveals CFTR-dependent dysregulation of type I IFN signaling in activated cystic fibrosis macrophages
Science Advances ( IF 13.6 ) Pub Date : 2023-05-26 , DOI: 10.1126/sciadv.adg5128
Jonathan L Gillan 1 , Mithil Chokshi 2 , Gareth R Hardisty 1 , Sara Clohisey Hendry 3 , Daniel Prasca-Chamorro 2 , Nicola J Robinson 1 , Benjamin Lasota 2 , Richard Clark 4 , Lee Murphy 4 , Moira K B Whyte 1 , J Kenneth Baillie 3 , Donald J Davidson 1 , Gang Bao 2 , Robert D Gray 1
Affiliation  

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.

中文翻译:

CAGE 测序揭示了在活化的囊性纤维化巨噬细胞中 I 型 IFN 信号传导依赖于 CFTR 的失调

强烈的、无法解决的气​​道炎症反应导致囊性纤维化 (CF) 中的破坏性肺病。巨噬细胞免疫功能失调可能是控制 CF 肺病进展的一个关键方面,但其潜在机制尚不完全清楚。我们使用以 5' 端为中心的转录组测序来分析铜绿假单胞菌LPS 激活的人类 CF 巨噬细胞,显示 CF 和非 CF 巨噬细胞在基线和激活后部署明显不同的转录程序。这包括相对于健康对照,在激活的患者细胞中 I 型 IFN 信号反应显着减弱,这在患者细胞中使用 CFTR 调节剂进行体外治疗并通过 CRISPR-Cas9 基因编辑来纠正患者来源的 iPSC 巨噬细胞中的 F508del 突变时是可逆的。这些发现说明了人类 CF 巨噬细胞中先前未发现的免疫缺陷,该缺陷依赖于 CFTR 且可通过 CFTR 调节剂逆转,从而为寻找 CF 的有效抗炎干预措施提供了新途径。
更新日期:2023-05-26
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