CD200 signaling mediates the interactions of neurons and endothelia with circulating leukocytes in stroke

项目总结 免疫反应是导致缺血的一个基本病理生理过程。 脑部受伤。控制免疫反应可以减轻中风和中风的延迟性损伤 具有相当大的翻译价值。CD200与其受体CD200R结合，CD200R在免疫细胞上表达 细胞。这会形成内源性抑制信号，减少免疫细胞的激活。这个 传统观点认为神经元-小胶质细胞CD200-CD200R相互作用是抑制 有害的免疫激活越来越受到质疑，因为越来越多的数据表明 CD200R在外周免疫细胞上表达，但在成人小胶质细胞上不表达。在这份提案中，我们 假设CD200-CD200R信号轴抑制外周免疫细胞的动员 且CD200-CD200R相互作用中断将加剧中枢(大脑)和 外周免疫反应。我们将从两端具体检查CD200-CD200R轴，通过 操纵CD200或CD200R以确定对外周免疫细胞激活的影响 以及中风伤。在目标1中，我们将使用由全球 CD200R基因敲除和GFP+小鼠，以确定外周和中枢(脑)CD200- CD200R信号对中风预后的影响。目的2研究内皮细胞CD200信号转导通路在血管内皮细胞中的作用 外周血白细胞在缺血脑内的迁移。脑内皮细胞CD200基因敲除(由AAV-BR1-Cre敲除 病毒)和Lenti-CD200病毒(与内皮细胞特异性启动子钙粘连蛋白5偶联)转染小鼠 分别检测内皮细胞CD200表达下调和上调对免疫功能的影响 对中风的反应。目的3将评估神经元CD200信号在卒中后炎症中的作用 以及中风的结果。神经性CD200 CKO小鼠(CD200fl/fl：eno2-Cre)和Lenti-CD200病毒对神经细胞的影响 将使用启动子烯醇化酶2(Eno2)。随着CD200-CD200R在各种不同的信号中发挥作用 神经炎性疾病，建议的项目将开辟CD200-CD200R研究的新领域 不仅在中风，而且在其他中枢神经系统疾病中也是如此。

PROJECT SUMMARY Immune responses are a fundamental pathophysiological process that significantly contribute to ischemic brain injury. Holding the immune response in check can alleviate the delayed injury seen in stroke and has considerable translational value. CD200 binds to its receptor, CD200R, that is expressed on immune cells. This forms an endogenous inhibitory signal and reduces the activation of immune cells. The traditional notion that the neuronal-microglial CD200-CD200R interaction is the key to suppressing deleterious immune activation has been increasingly questioned, as accumulating data has shown that the CD200R is expressed on peripheral immune cells but not on adult microglia. In this proposal we hypothesize that the CD200-CD200R signaling axis inhibits mobilization of peripheral immune cells after stroke, and that interruption of CD200-CD200R interaction will exacerbate both central (brain) and peripheral immune responses. We will specifically examine the CD200-CD200R axis from both ends, by manipulating either CD200 or the CD200R to determine the effects on peripheral immune cell activation and stroke injury. In Aim 1, we will use a bone marrow chimera mouse model generated from global CD200R knockout and GFP+ mice, to determine the contribution of peripheral vs. central (brain) CD200- CD200R signaling to stroke outcomes. Aim 2 will investigate the effect of endothelial CD200 signaling on peripheral leukocyte migration in the ischemic brain. Brain endothelial CD200 knockdown (by AAV-BR1-Cre virus) and lenti-CD200 virus (conjugated with endothelial specific promotor Cadherin 5) transfected mice will be used to examine the effects of down-/up-regulation of endothelial CD200 respectively on immune responses to stroke. Aim 3 will evaluate the role of neuronal CD200 signaling in post-stroke inflammation and stroke outcomes. Neuronal CD200 CKO mice (CD200fl/fl:Eno2-Cre) and lenti-CD200 virus on neuronal promotor Enolase 2 (Eno2) will be used. As CD200-CD200R signaling functions in various neuroinflammatory diseases, the proposed project will open up a new area of CD200-CD200R research not only in stroke, but also in other central nervous system disorders.