Class IA Phosphoinositide 3-Kinase β and δ Regulate Neutrophil Oxidase Activation in Response to Aspergillus fumigatus Hyphae
Class IA Phosphoinositide 3-Kinase β and δ Regulate Neutrophil Oxidase Activation in Response to Aspergillus fumigatus Hyphae
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DOI：
10.4049/jimmunol.1002268
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发表时间：
2011-03-01
影响因子：
4.4
通讯作者：
Hawkins, Phillip T.
中科院分区：
文献类型：
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作者：
Boyle, Keith B.;Gyori, David;Hawkins, Phillip T.
对普遍存在的真菌烟曲霉的有效免疫应答依赖于NADPH氧化酶产生活性氧（ROS）。氧化酶缺乏的人和小鼠对侵袭性曲霉病的急性敏感性证明了这一点。中性粒细胞在感染后不久被募集到肺部，并通过吞噬分生孢子和以ROS依赖的方式介导萌发菌丝的细胞外杀伤来响应。然而，调控菌丝产生活性氧的信号机制知之甚少。PI 3 K是许多细胞过程的重要调节剂，最近的许多工作描述了不同I类PI 3 K亚型的独特作用。我们通过活细胞成像显示，I类PI 3 Ks的脂质产物在菌丝结合的中性粒细胞质膜上积累。此外，我们使用药理学和遗传学方法来证明PI 3 K β和PI 3 K δ在ROS和小鼠嗜中性粒细胞对曲霉菌菌丝的扩散反应中的重要但重叠的作用。菌丝诱导的ROS反应基本上被共同的β 2-整联蛋白亚基CD 18的缺失所抑制，Dectin-1仅具有次要的冗余作用。然而，需要添加可溶性藻葡聚糖加上CD 18的遗传缺失来显著抑制PI 3 K效应蛋白激酶B的活化。菌丝ROS反应也完全依赖于Syk的存在，而不是其ITAM含有衔接蛋白FcR γ或DAP 12，和Vav家族的Rac-鸟嘌呤核苷酸交换因子。这些结果开始定义控制中性粒细胞ROS对A.烟曲霉菌丝免疫学杂志，2011，186：2978-2989。
An effective immune response to the ubiquitous fungus Aspergillus fumigatus is dependent upon production of reactive oxygen species (ROS) by the NADPH oxidase. This is evidenced by the acute sensitivity of oxidase-deficient humans and mice to invasive aspergillosis. Neutrophils are recruited to the lungs shortly postinfection and respond by phagocytosing conidia and mediating extracellular killing of germinated hyphae in a ROS-dependent manner. However, the signaling mechanisms regulating the generation of ROS in response to hyphae are poorly understood. PI3Ks are important regulators of numerous cellular processes, with much recent work describing unique roles for the different class I PI3K isoforms. We showed by live-cell imaging that the lipid products of class I PI3Ks accumulated at the hyphal-bound neutrophil plasma membrane. Further, we used pharmacological and genetic approaches to demonstrate essential, but overlapping, roles for PI3K beta and PI3K delta in the ROS and spreading responses of murine neutrophils to Aspergillus hyphae. Hyphal-induced ROS responses were substantially inhibited by deletion of the common beta 2-integrin subunit CD18, with only a minor, redundant role for Dectin-1. However, addition of soluble algal glucans plus the genetic deletion of CD18 were required to significantly inhibit activation of the PI3K-effector protein kinase B. Hyphal ROS responses were also totally dependent on the presence of Syk, but not its ITAM-containing adaptor proteins FcR gamma or DAP12, and the Vav family of Rac-guanine nucleotide exchange factors. These results start to define the signaling network controlling neutrophil ROS responses to A. fumigatus hyphae. The Journal of Immunology, 2011, 186: 2978-2989.