Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation.
Loss of CFTR function in macrophages alters the cell transcriptional program and delays lung resolution of inflammation.
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巨噬细胞中囊性纤维化跨膜传导调节因子（CFTR）功能丧失会改变细胞转录程序，并延缓肺部炎症的消退。
DOI：
10.3389/fimmu.2023.1242381
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发表时间：
2023
影响因子：
7.3
通讯作者：
Wang, Guoshun
中科院分区：
文献类型：
--
作者：
Wellems, Dianne;Hu, Yawen;Jennings, Scott;Wang, Guoshun
关键词：
囊性纤维化（CF）是一种常染色体隐性遗传病，由CF跨膜传导调节因子（CFTR）基因突变引起。CF的最严重病理发生在肺中，表现为慢性细菌感染、持续性嗜酸性炎症和粘液脓性气道阻塞。尽管对CF原发性缺陷和由此产生的临床后遗症的认识不断增加，但CFTR功能丧失与嗜酸性炎症之间的关系仍不完全清楚。在这里，我们报道了巨噬细胞CFTR功能的丧失导致了肺部炎症的扩展。经腹腔接种铜绿假单胞菌后，巨噬细胞特异性Cftr基因敲除小鼠（Mac-CF）能够建立有效的宿主防御机制，以清除细菌感染。然而，接种后三天，Mac-CF肺表现出显著更多的中性粒细胞浸润和更高水平的炎性细胞因子，表明Mac-CF小鼠的炎症消退较慢。单细胞RNA测序显示，巨噬细胞中CFTR的缺失改变了细胞转录程序，影响细胞炎症和免疫反应、抗氧化系统和线粒体呼吸。因此，巨噬细胞中CFTR功能的丧失影响细胞稳态，导致对感染的细胞应答失调，这可能加剧CF肺病。
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) gene. The most severe pathologies of CF occur in the lung, manifesting as chronic bacterial infection, persistent neutrophilic inflammation, and mucopurulent airway obstruction. Despite increasing knowledge of the CF primary defect and the resulting clinical sequelae, the relationship between the CFTR loss of function and the neutrophilic inflammation remains incompletely understood. Here, we report that loss of CFTR function in macrophages causes extended lung inflammation. After intratracheal inoculation with Pseudomonas aeruginosa, mice with a macrophage-specific Cftr-knockout (Mac-CF) were able to mount an effective host defense to clear the bacterial infection. However, three days post-inoculation, Mac-CF lungs demonstrated significantly more neutrophil infiltration and higher levels of inflammatory cytokines, suggesting that Mac-CF mice had a slower resolution of inflammation. Single-cell RNA sequencing revealed that absence of CFTR in the macrophages altered the cell transcriptional program, affecting the cell inflammatory and immune responses, antioxidant system, and mitochondrial respiration. Thus, loss of CFTR function in macrophages influences cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease.
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影响因子：
12.8
作者：
Di Pietro, Caterina;Oz, Hasan H.;Zhang, Ping-xia;Cheng, Ee-chun;Martis, Valentino;Bonfield, Tracey L.;Kelley, Thomas J.;Jubin, Ronald;Abuchowski, Abraham;Krause, Diane S.;Egan, Marie E.;Murray, Thomas S.;Bruscia, Emanuela M.
通讯作者：
Bruscia, Emanuela M.
影响因子：
7.7
作者：
Domingo-Gonzalez, Racquel;Zanini, Fabio;Alvira, Cristina M.
通讯作者：
Alvira, Cristina M.
DOI：
10.1164/rccm.202106-1426oc
发表时间：
2022-04-01
影响因子：
24.7
作者：
Gabillard-Lefort, Claudie;Casey, Michelle;Reeves, Emer P.
通讯作者：
Reeves, Emer P.
影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
30.5
作者：
Aegerter, Helena;Kulikauskaite, Justina;Wack, Andreas
通讯作者：
Wack, Andreas