Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells
Induction of Type I Interferon Signaling by Pseudomonas aeruginosa Is Diminished in Cystic Fibrosis Epithelial Cells
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DOI：
10.1165/rcmb.2011-0080oc
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发表时间：
2012-01-01
影响因子：
6.4
通讯作者：
Prince, Alice
中科院分区：
文献类型：
--
作者：
Parker, Dane;Cohen, Taylor S.;Prince, Alice
囊性纤维化（CF）感染的临床表现仅限于肺部，涉及的病原体数量有限，表明粘膜免疫存在特定缺陷。我们假设囊性纤维化跨膜电导调节因子（CTFR）突变可能影响气道上皮细胞中 I 型干扰素信号的激活，该信号在免疫监视中发挥作用并启动免疫细胞的招募和激活。为了响应铜绿假单胞菌感染，小鼠肺中的 Ifnb 被诱导超过 100 倍，并且 STAT1 的磷酸化同样由预期的 TLR4/TRIF/MD2/TBK1 级联诱导。铜绿假单胞菌对 CF (IB3) 细胞和对照 (C-38) 人细胞系的刺激类似地导致 IFN-β 的诱导，但在 CF 气道细胞中的程度显着较低。 I 型 IFN 信号减弱的潜在后果在铜绿假单胞菌肺炎鼠模型中得到证实，聚肌胞苷酸预处理可显着增强细菌清除率，并与肺中成熟 CD11c(+)/CD86(+) 树突状细胞 (DC) 数量的增加相关。使用来自铜绿假单胞菌刺激的CF或对照细胞系的培养物上清液，我们同样证明了与正常上皮细胞培养物上清液相比，通过与CF一起孵育，人单核细胞衍生的DC的活化减少，这依赖于IFN-β。这些观察结果表明，气道上皮细胞中 CFTR 的功能障碍可能导致 CF 气道中的免疫监视受损，并导致铜绿假单胞菌定植。
The clinical manifestations of infection in cystic fibrosis (CF) are restricted to the lung, and involve a limited number of pathogens, suggesting a specific defect in mucosal immunity. We postulated that cystic fibrosis transmembrane conductance regulator (CTFR) mutations could affect the activation of type I interferon signaling in airway epithelial cells, which function in immune surveillance and initiate the recruitment and activation of immune cells. In response to infection with Pseudomonas aeruginosa, Ifnb was induced more than 100-fold in the murine lung, and the phosphorylation of STAT1 was similarly induced by the expected TLR4/TRIF/MD2/TBK1 cascade. The stimulation by P. aeruginosa of CF (IB3) cells and control (C-38) human cell lines similarly resulted in the induction of IFN-beta, but to a significantly lower extent in CF airway cells. The potential consequences of diminished type I IFN signaling were demonstrated in a murine model of P. aeruginosa pneumonia, pretreatment with polyinosinic: polycytidylic acid significantly enhanced bacterial clearance and correlated with increased numbers of mature CD11c(+)/CD86(+) dendritic cells (DCs) in the lung. Using culture supernatants from CF or control cell lines stimulated with P. aeruginosa, we similarly demonstrated the diminished activation of human monocyte-derived DCs by incubation with CF compared with normal epithelial cell culture supernatants, which was dependent on IFN-beta. These observations suggest that dysfunction of the CFTR in airway epithelial cells may contribute to impaired immune surveillance in the CF airway and resultant colonization by P. aeruginosa.