Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster.
Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster.
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DOI：
10.1038/sigtrans.2016.32
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发表时间：
2016
影响因子：
39.3
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Li R;Fang L;Pu Q;Lin P;Hoggarth A;Huang H;Li X;Li G;Wu M
多效性 Src 激酶 Lyn 在肺泡巨噬细胞抵抗细菌感染的宿主防御中发挥着关键作用，但 Lyn 介导的炎症反应的潜在机制在很大程度上仍然难以捉摸。使用小鼠铜绿假单胞菌感染模型，我们观察到与野生型同窝小鼠相比，Lyn−/− 小鼠表现出严重的肺损伤和增强的炎症反应。我们证明 Lyn 通过其 SH2 和 SH3 结构域与 IL-6 受体和细胞骨架蛋白 Ezrin 相互作用来发挥这种免疫功能。 Lyn 的耗尽会导致 STAT3 过度激活，并增强含有 Src 同源 2 的肌醇 5 磷酸酶 1 (SHIP-1) 表达。 Lyn−/− 小鼠中 SHIP-1 的缺失（双敲除）可促进小鼠存活并减少铜绿假单胞菌感染期间的炎症反应，揭示了 Lyn 缺陷中致命感染表型的拯救。从机制上讲，SHIP-1 的缺失会减少 NF-κB 依赖性细胞因子的产生，并通过不依赖于 TLR4 的 PI3K/Akt 途径抑制 MAP 激酶的激活。这些发现表明，Lyn 通过肺泡巨噬细胞中的 SHIP-1 和 IL-6/STAT3 信号通路调节宿主对铜绿假单胞菌感染的免疫反应。
The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection, but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive. Using mouse Pseudomonas aeruginosa infection models, we observed that Lyn−/− mice manifest severe lung injury and enhanced inflammatory responses, compared with wild-type littermates. We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains. Depletion of Lyn results in excessive STAT3 activation, and enhanced the Src homology 2-containing inositol-5-phopsphatase 1 (SHIP-1) expression. Deletion of SHIP-1 in Lyn−/− mice (double knockout) promotes mouse survival and reduces inflammatory responses during P. aeruginosa infection, revealing the rescue of the deadly infectious phenotype in Lyn deficiency. Mechanistically, loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway. These findings reveal Lyn as a regulator for host immune response against P. aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages.
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影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
4.4
作者：
Kannan, Shibichakravarthy;Audet, Aaron;Wu, Min
通讯作者：
Wu, Min