Leukocyte interaction with immunological interfaces of the brain after stroke

炎症级联反应在缺血性脑损伤后继发性神经元损伤中起重要作用。中风后神经炎症的一个关键机制是外周免疫细胞侵入受损的大脑。本课题组和其他研究者以往的研究主要是探讨白细胞侵入脑实质的机制及其神经毒性作用。最近的研究结果表明，白细胞-内皮细胞相互作用在诱导中风后神经炎症的重要作用。尽管如此，循环白细胞激活内皮细胞的机制及其对中风病理生理学的作用仍不清楚。此外，已经表明，神经炎性级联反应可能被诱导，而不需要白细胞穿过内皮的实质迁移，这表明了替代的浸润机制。有趣的是，来自我们小组的未发表的数据表明脉络丛作为白细胞向缺血脑的替代侵入途径的潜在作用。脉络丛的一个关键作用是在原发性自身免疫性或感染性脑疾病的模型中确定的;然而，脉络丛在缺血性卒中中的作用以前没有分析过。因此，本研究的目的是研究外周血白细胞与（内皮）血脑屏障以及（上皮）脉络丛的免疫界面的相互作用，作为缺血性脑损伤后白细胞侵袭的替代途径。具体来说，我们想分析以下几个方面：1） 不同卒中模型中白细胞优先侵袭的特定解剖部位的特征。（二） 脉络丛作为白细胞进入缺血脑的另一种侵袭途径的评价。第三章 缺血后白细胞-内皮细胞相互作用激活内皮细胞的机制分析。四、 测试抑制内皮激活治疗急性卒中后继发性神经元丢失的治疗潜力。更好地了解卒中后全身免疫细胞与大脑的相互作用将有助于开发更特异的神经炎症药物靶点，并确定可能从此类方法中获益最多的卒中患者。

Inflammatory cascades contribute significantly to secondary neuronal damage after ischemic brain injury. A key mechanism of post-stroke neuroinflammation is the invasion of peripheral immune cells into the injured brain. Previous research by our group and others has mainly investigated the mechanisms of leukocyte invasion to the brain parenchyma and their neurotoxic function. Recent results indicate an important role of leukocyte-endothelial interactions in the induction of post-stroke neuroinflammation. Still, the mechanisms of endothelial activation by circulating leukocytes and its contribution to the pathophysiology of stroke is barely understood. Moreover, it has been shown that neuroinflammatory cascades might be induced without the necessity of parenchymal transmigration of the leukocytes across the endothelium suggesting alternative infiltration mechanisms. Interestingly, unpublished data from our group indicates a potential role for the choroid plexus as an alternative invasion route of leukocytes to the ischemic brain. A key role of the choroid plexus was identified in models of primary autoimmune or infectious diseases of the brain; yet, the role of the choroid plexus in ischemic stroke was previously not analyzed. Therefore, the aim of this study is to investigate the interaction of peripheral leukocytes with the immunological interfaces of the (endothelial) blood-brain barrier as well as the (epithelial) choroid plexus as an alternative leukocyte invasion route after ischemic brain injury. Specifically, we want to analyze the following aspects:1) Characterization of specific anatomical sites of preferential leukocyte invasion in differing stroke models. 2) Evaluation of the choroid plexus as an alternative invasion route for leukocytes into the ischemic brain. 3) Analysis of the mechanisms of endothelial activation by postischemic leukocyte-endothelial interaction. 4) Testing the therapeutic potential of inhibiting endothelial activation for the treatment of secondary neuronal loss after acute stroke.The better understanding of the interaction of systemic immune cells with the brain after stroke will help to develop more specific neuroinflammatory drug targets and define stroke patients that might benefit the most from such approaches.