The Role of Monocytic Cells in Long-Term Post-Stroke Outcome

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The translational roadblock in stroke research may in part relate to the fact that the interplay of different pathomechanisms is more complex than previously thought. In particular, inflammatory processes which are involved in cellular damage during the early phase of brain ischemia may promote recovery at later stages. Our proposal tests the hypothesis that the pathogenetic role of resident microglia versus invading monocytes diverges markedly and changes time-dependently after brain ischemia. We will use bone-marrow (BM) chimerism, viral vectors, and genetically modified mice (e.g. Ccr2RFP::Cx3cr1GFP mice) to study differences between microglia and invading monocytes. In dual-color experiments, we will trace the influx of red fluorescently labeled monocytes into the ischemic brain of mice harboring microglia expressing GFP (MacGreen mouse model). This approach not only permits convenient detection of microglia and invaded macrophages for histological and physiological analyses, but also facilitates isolation for functional assays and transcriptional profiling. Then, we will interfere with the invasion of inflammatory cells into the brain using genetically altered BM (e.g. gelsolin-deficient BM resulting in impaired migration into ischemic brain parenchyma, P-selectin glycoprotein ligand-1 [PSGL-1] deficient BM resulting in impaired tethering/adhesion). We will specifically focus on complex endpoints including secondary neurodegeneration, cellular plasticity and neurobehavioral outcomes.