Neutrophil-mediated phagocytic host defense defect in myeloid Cftr-inactivated mice.
Neutrophil-mediated phagocytic host defense defect in myeloid Cftr-inactivated mice.
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DOI：
10.1371/journal.pone.0106813
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Ng HP;Zhou Y;Song K;Hodges CA;Drumm ML;Wang G
囊性纤维化是一种常见的致命遗传性疾病，由编码cAMP激活的氯离子通道的CFTR基因突变引起。该病的一个突出表现是肺部持续的细菌感染和炎症，占CF死亡率的90%以上。中性粒细胞介导的吞噬细胞先天免疫是否存在导致宿主肺防御失败的内在缺陷一直存在争议。在这里，我们比较了吞噬体cftr靶向、次氯酸的产生和微生物对髓系cftr灭活(髓系cftr−/−)小鼠和未灭活对照(Cftrfl10)小鼠中性粒细胞的杀灭作用。我们发现缺失外显子-10的突变体CFTR不能靶向中性粒细胞吞噬小体。这种功能障碍导致吞噬体内HOCl的产生和中性粒细胞的微生物杀灭受到损害。在体内，致死剂量的铜绿假单胞菌肺部感染导致髓系CF小鼠的死亡率显著高于对照组。髓系cftr−/−肺细菌清除不足，中性粒细胞炎症持续，早期免疫向晚期免疫转变停滞。这些表现概括了人类CF肺的症状。这些数据表明，髓系CFTR的表达对正常的宿主肺防御是至关重要的。中性粒细胞的CFTR功能障碍损害了吞噬细胞的天然免疫功能，这可能使CFF肺更容易受到感染。
Cystic fibrosis (CF) is a common and deadly inherited disease, caused by mutations in the CFTR gene that encodes a cAMP-activated chloride channel. One outstanding manifestation of the disease is the persistent bacterial infection and inflammation in the lung, which claims over 90% of CF mortality. It has been debated whether neutrophil-mediated phagocytic innate immunity has any intrinsic defect that contributes to the host lung defense failure. Here we compared phagosomal CFTR targeting, hypochlorous acid (HOCl) production, and microbial killing of the neutrophils from myeloid Cftr-inactivated (Myeloid-Cftr−/−) mice and the non-inactivated control (Cftrfl10) mice. We found that the mutant CFTR that lacked Exon-10 failed to target to the neutrophil phagosomes. This dysfunction resulted in impaired intraphagosomal HOCl production and neutrophil microbial killing. In vivo lung infection with a lethal dose of Pseudomonas aeruginosa caused significantly higher mortality in the myeloid CF mice than in the controls. The myeloid-Cftr−/− lungs were deficient in bacterial clearance, and had sustained neutrophilic inflammation and stalled transition from early to late immunity. These manifestations recapitulated the symptoms of human CF lungs. The data altogether suggest that myeloid CFTR expression is critical to normal host lung defense. CFTR dysfunction in neutrophils compromises the phagocytic innate immunity, which may predispose CF lungs to infection.
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