Leukocyte interaction with immunological interfaces of the brain after stroke

• Applicant: Professor Dr. Arthur Liesz
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 259826455

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 Interestingly, unpublished data from our group indicates a potential role for the choroid plexus as an alternative invasion route of leukocytes to the ischemic brain.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

• DFG Programme: Research Grants