Increased Susceptibility to Pulmonary Pseudomonas Infection in Splunc1 Knockout Mice
Increased Susceptibility to Pulmonary Pseudomonas Infection in Splunc1 Knockout Mice
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DOI：
10.4049/jimmunol.1202340
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发表时间：
2013-10-15
影响因子：
4.4
通讯作者：
Di, Y. Peter
中科院分区：
文献类型：
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作者：
Liu, Yanyan;Di, Marissa E.;Di, Y. Peter
气道上皮是宿主抵御病原体的第一道防线。短腭、肺和鼻上皮克隆（SPLUNC） 1蛋白分泌于呼吸道，是细菌/通透性增加（BPI）折叠蛋白家族的成员，与BPI样蛋白具有结构相似性。基于其与bpi的同源性以及SPLUNC1在粘膜下腺浆液细胞和上呼吸道表面上皮细胞中的限制性表达，SPLUNC1被认为在宿主防御中具有抗菌活性。SPLUNC1也被报道具有表面活性剂特性，这可能有助于抗生物膜防御。本研究的目的是确定SPLUNC1在铜绿假单胞菌感染后的体内功能，并通过SPLUNC1基因切除的敲除（KO）小鼠模型阐明其潜在机制。与野生型小鼠相比，Splunc1 KO小鼠的死亡率加快，对铜绿假单胞菌感染的易感性增加，存活率显著降低，细菌负担增加，组织损伤加重，促炎细胞因子水平升高。Splunc1 KO小鼠中性粒细胞浸润增加，同时趋化因子水平升高，包括Cxcl1、Cxcl2和Ccl20。此外，Splunc1 KO小鼠肺中几种上皮分泌蛋白和抗菌分子的表达明显受到抑制。小鼠气道上皮Splunc1缺失也导致铜绿假单胞菌生物膜形成增加。综上所述，我们的研究结果支持Splunc1在小鼠气道中的消融会影响粘膜纤毛清除，导致假单胞菌引起的呼吸道感染期间先天免疫反应降低。
The airway epithelium is the first line of host defense against pathogens. The short palate, lung, and nasal epithelium clone (SPLUNC) 1 protein is secreted in respiratory tracts and is a member of the bacterial/permeability increasing (BPI) fold-containing protein family, which shares structural similarities with BPI-like proteins. On the basis of its homology with BPIs and restricted expression of SPLUNC1 in serous cells of submucosal glands and surface epithelial cells of the upper respiratory tract, SPLUNC1 is thought to possess antimicrobial activity in host defense. SPLUNC1 is also reported to have surfactant properties, which may contribute to anti-biofilm defenses. The objective of this study was to determine the in vivo functions of SPLUNC1 following Pseudomonas aeruginosa infection and to elucidate the underlying mechanism by using a knockout (KO) mouse model with a genetic ablation of Splunc1. Splunc1 KO mice showed accelerated mortality and increased susceptibility to P. aeruginosa infection with significantly decreased survival rates, increased bacterial burdens, exaggerated tissue injuries, and elevated proinflammatory cytokine levels as compared with those of their wild-type littermates. Increased neutrophil infiltration in Splunc1 KO mice was accompanied by elevated chemokine levels, including Cxcl1, Cxcl2, and Ccl20. Furthermore, the expression of several epithelial secretory proteins and antimicrobial molecules was considerably suppressed in the lungs of Splunc1 KO mice. The deficiency of Splunc1 in mouse airway epithelium also results in increased biofilm formation of P. aeruginosa. Taken together, our results support that the ablation of Splunc1 in mouse airways affects the mucociliary clearance, resulting in decreased innate immune response during Pseudomonas-induced respiratory infection.