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。卒中后神经炎症的一个关键机制是外周免疫细胞侵入损伤的大脑。本课题组等前期研究主要探讨白细胞侵袭脑实质的机制及其神经毒性功能。最近的研究结果表明，白细胞内皮相互作用在卒中后神经炎症诱导中的重要作用。然而，内皮细胞活化循环白细胞的机制及其对中风病理生理的贡献几乎不为人所知。此外，研究表明，神经炎症级联反应可能不需要白细胞穿过内皮细胞的实质迁移就能诱导，这提示了其他浸润机制。有趣的是，我们小组未发表的数据表明脉络膜丛作为白细胞入侵缺血性脑的替代途径的潜在作用。脉络膜丛在原发性自身免疫性或传染性脑疾病模型中的关键作用已被确定；然而，脉络膜丛在缺血性中风中的作用以前没有被分析过。因此，本研究的目的是研究外周白细胞与（内皮）血脑屏障和（上皮）脉络膜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另一种途径。具体来说，我们想分析以下几个方面：1)在不同的中风模型中，白细胞优先侵袭的特定解剖部位的特征。2)脉络膜丛作为白细胞进入缺血性脑的另一种侵袭途径的评价。3)缺血后白细胞-内皮相互作用对内皮活化的机制分析。4)测试抑制内皮细胞活化治疗急性脑卒中后继发性神经元丢失的治疗潜力。更好地了解中风后全身免疫细胞与大脑的相互作用将有助于开发更具体的神经炎症药物靶点，并确定中风患者可能从这些方法中获益最多。

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 Interestingly, unpublished data from our group indicates a potential role for the choroid plexus as an alternative invasion route of leukocytes to the ischemic brain.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.