Leukocyte interaction with immunological interfaces of the brain after stroke

炎性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受损的大脑。以前我们等人的研究主要是研究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，白细胞与内皮细胞的相互作用在卒中后神经炎症的诱导中起着重要作用。然而，循环白细胞激活血管内皮细胞的机制及其在卒中病理生理学中的作用仍鲜为人知。此外，研究还表明，神经炎性级联反应可以在不需要白细胞跨内皮实质移位的情况下被诱导，这暗示了替代的渗透机制。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对缺血脑的另一种侵袭途径具有潜在的作用。脉络丛在原发自身免疫性或脑感染性疾病模型中的关键作用已被确认；然而，脉络丛在缺血性中风中的作用之前并未被分析。因此，本研究的目的是探讨缺血性脑损伤后外周血白细胞与(内皮)血脑屏障和(上皮)脉络丛免疫界面的相互作用，作为白细胞侵袭的替代途径。具体地说，我们想要分析以下几个方面：1)在不同的卒中模型中，优先白细胞入侵的特定解剖位置的特征。2)评价脉络丛作为白细胞侵入脑缺血的替代途径。3)分析缺血后白细胞与内皮细胞相互作用激活内皮细胞的机制。4)测试抑制血管内皮细胞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具特异性的神经炎性药物靶点，并确定可能从此类方法中受益最大的中风患者。

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 Interestingly, unpublished data from our group indicates a potential role for the choroid plexus as an alternative invasion route of leukocytes to the ischemic brain.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