The Effects of IFN-λ on Epithelial Barrier Function Contribute to Klebsiella pneumoniae ST258 Pneumonia
The Effects of IFN-λ on Epithelial Barrier Function Contribute to Klebsiella pneumoniae ST258 Pneumonia
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DOI：
10.1165/rcmb.2018-0021oc
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发表时间：
2019-02-01
影响因子：
6.4
通讯作者：
Prince, Alice
中科院分区：
文献类型：
--
作者：
Ahn, Danielle;Wickersham, Matthew;Prince, Alice
IFN-λ和IL-22，共享共受体IL-10 RB的细胞因子，都在肺炎克雷伯氏菌ST 258（KP 35）肺炎的过程中被诱导。已知IL-22保护粘膜屏障，而IFN-λ对粘膜的作用尚未确定。我们推测IFN-λ在调节气道上皮屏障以促进细胞运输至感染部位中起作用。响应于IFN-λ，中性粒细胞穿过极化的气道上皮细胞单层的迁移增加，与上皮完整性降低一致。KP 35感染增加了上皮细胞的通透性，用IFN-λ预处理放大了这种作用，并促进了细菌的迁移。IFN-λ的这些作用在体内得到了证实，因为缺乏IFN-λ受体（Ifnlr 1（-l-））的小鼠在KP 35肺炎的鼠模型中受到保护而免于菌血症。相反，上皮屏障的完整性受到IL-22的保护，随后在体外损害中性粒细胞和细菌的迁移。在感染过程中比IFN-λ产生更晚观察到体内IL-22的最大表达，在48小时时由募集的免疫细胞产生高水平的IL-22，这与上皮屏障恢复中的作用一致。这两个相关的细胞因子的不同和相反的表达表明在宿主对KP 35感染的反应中存在调节的相互作用。IFN-λ信号传导的主要生理效应是上皮屏障完整性的降低，这促进免疫细胞募集，但也使K。肺炎侵袭。
IFN-lambda and IL-22, cytokines that share the coreceptor IL-10RB, are both induced over the course of Klebsida pneumoniae ST258 (KP35) pneumonia. IL-22 is known to protect mucosal barriers, whereas the effects of IFN-lambda on the mucosa are not established. We postulated that IFN-lambda plays a role in regulating the airway epithelial barrier to facilitate cellular trafficking to the site of infection. In response to IFN-lambda, the transmigration of neutrophils across a polarized monolayer of airway epithelial cells was increased, consistent with diminished epithelial integrity. KP35 infection increased epithelial permeability, and pretreatment with IFN-lambda amplified this effect and facilitated bacterial transmigration. These effects of IFN-lambda were confirmed in vivo, in that mice lacking the receptor for IFN-lambda (Ifnlr1(-l-)) were protected from bacteremia in a murine model of KP35 pneumonia. Conversely, the integrity of the epithelial barrier was protected by IL-22, with subsequent impairment of neutrophil and bacterial transmigration in vitro. Maximal expression of IL-22 in vivo was observed later in the course of infection than IFN-lambda production, with high levels of IL-22 produced by recruited immune cells at 48 hours, consistent with a role in epithelial barrier recovery. The divergent and opposing expression of these two related cytokines suggests a regulated interaction in the host response to KP35 infection. A major physiological effect of IFN-lambda signaling is a decrease in epithelial barrier integrity, which facilitates immune cell recruitment but also enables K. pneumoniae invasion.