Interferon regulatory factor 8 regulates expression of acid ceramidase and infection susceptibility in cystic fibrosis.
Interferon regulatory factor 8 regulates expression of acid ceramidase and infection susceptibility in cystic fibrosis.
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DOI：
10.1016/j.jbc.2021.100650
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Gulbins E
中科院分区：
文献类型：
--
作者：
Gardner AI;Wu Y;Verhaegh R;Liu Y;Wilker B;Soddemann M;Keitsch S;Edwards MJ;Haq IJ;Kamler M;Becker KA;Brodlie M;Gulbins E
大多数囊性纤维化患者患有急性和慢性肺部感染，细菌感染往往决定了他们的生活质量和预期。先前的研究表明，CF上皮细胞中酸性神经酰胺酶的下调导致神经酰胺的增加和鞘氨醇的减少。鞘氨醇可以杀死许多细菌病原体，而鞘氨醇的下调似乎决定了囊性纤维化小鼠和患者的感染易感性。目前尚不清楚囊性纤维化跨膜传导调节因子(CFTR)的缺乏如何与人和小鼠CF上皮细胞酸性神经酰胺酶的显着下调有关。在这里，我们使用定量聚合酶链式反应、蛋白质印迹分析和酶活性测量来研究IRF8在酸性神经酰胺酶调节中的作用。我们报道，CFTR/CFTR的遗传缺陷或功能抑制导致干扰素调节因子8(IRF8)上调，伴随而来的是CF的酸性神经酰胺酶表达下调，以及人或小鼠气管和支气管上皮细胞神经酰胺的增加和鞘氨醇水平的降低。CRISPR/Cas9或siRNA介导的IRF8下调可阻止CF上皮细胞酸性神经酰胺酶、神经酰胺和鞘氨醇的变化，恢复对铜绿假单胞菌感染的抵抗力，铜绿假单胞菌是CF患者肺部感染最重要和最常见的病原体之一。这些研究表明，CFTR缺陷通过上调IRF8导致酸性神经酰胺酶下调，IRF8是控制CF细胞感染易感性的中心途径。
Most patients with cystic fibrosis (CF) suffer from acute and chronic pulmonary infections with bacterial pathogens, which often determine their life quality and expectancy. Previous studies have demonstrated a downregulation of the acid ceramidase in CF epithelial cells resulting in an increase of ceramide and a decrease of sphingosine. Sphingosine kills many bacterial pathogens, and the downregulation of sphingosine seems to determine the infection susceptibility of cystic fibrosis mice and patients. It is presently unknown how deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) connects to a marked downregulation of the acid ceramidase in human and murine CF epithelial cells. Here, we employed quantitative PCR, western blot analysis, and enzyme activity measurements to study the role of IRF8 for acid ceramidase regulation. We report that genetic deficiency or functional inhibition of CFTR/Cftr results in an upregulation of interferon regulatory factor 8 (IRF8) and a concomitant downregulation of acid ceramidase expression with CF and an increase of ceramide and a reduction of sphingosine levels in tracheal and bronchial epithelial cells from both human individuals or mice. CRISPR/Cas9- or siRNA-mediated downregulation of IRF8 prevented changes of acid ceramidase, ceramide, and sphingosine in CF epithelial cells and restored resistance to Pseudomonas aeruginosa infections, which is one of the most important and common pathogens in lung infection of patients with CF. These studies indicate that CFTR deficiency causes a downregulation of acid ceramidase via upregulation of IRF8, which is a central pathway to control infection susceptibility of CF cells.
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影响因子：
2.7
作者：
Fischer CL;Walters KS;Drake DR;Blanchette DR;Dawson DV;Brogden KA;Wertz PW
通讯作者：
Wertz PW
CftrTgH(neoim)Hgu 囊性纤维化小鼠模型中插入突变的不稳定性。
影响因子：
2.9
作者：
Charizopoulou, N;Jansen, S;Dorsch, M;Stanke, F;Dorin, JR;Hedrich, HJ;Tümmler, B
通讯作者：
Tümmler, B
DOI：
10.1016/j.bbrc.2017.12.137
发表时间：
2018-01-22
影响因子：
3.1
作者：
Azuma MM;Balani P;Boisvert H;Gil M;Egashira K;Yamaguchi T;Hasturk H;Duncan M;Kawai T;Movila A
通讯作者：
Movila A
DOI：
10.33594/000000194
发表时间：
2019-01-01
期刊：
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
影响因子：
--
作者：
Carstens, Henning;Schumacher, Fabian;Gulbins, Erich
通讯作者：
Gulbins, Erich
影响因子：
11.2
作者：
Hu X;Yang D;Zimmerman M;Liu F;Yang J;Kannan S;Burchert A;Szulc Z;Bielawska A;Ozato K;Bhalla K;Liu K
通讯作者：
Liu K