Dynamic interactions between ischemic stroke, immunity and the bone marrow

描述（由申请人提供）：骨髓最近被认为是中风后的关键反应者。作为造血的位点，它产生白细胞，其i）可以增强脑损伤中的组织损伤或愈合，以及ii）维持动脉粥样硬化斑块中的炎症，从而触发复发性中风。与此同时，白细胞可以防止感染。临床中风数据显示循环单核细胞和中性粒细胞水平增加，表明先天免疫激活。中风患者复发缺血性中风的风险更高， 事件（例如，复发性卒中），这可能是由于卒中相关的血管壁炎症和动脉粥样硬化形成的加速。中风后肺炎的高发病率伴有淋巴细胞计数下降，表明适应性免疫抑制。我们的初步数据表明，中风后先天免疫细胞供应增加会增强高脂血症小鼠的动脉粥样硬化（Nature 2012）。其机制目前尚不清楚;然而，从该修订申请中获得的新数据显示，卒中后骨髓中白细胞生成急剧增加。因此，我们建议测试的总体假设，缺血性脑和造血系统损伤和修复的演变过程中有重要的串扰。我们假设缺血性脑损伤激活了骨髓中的造血干细胞（HSC），并向髓系细胞谱系引入造血偏好。我们推测，祖细胞增殖增加将导致嗜中性粒细胞增多症和单核细胞增多症。基于文献中的初步数据和证据，我们假设这些细胞调节缺血性脑损伤内的炎症反应，并增加动脉粥样硬化斑块中的炎症。我们建议研究缺血性中风对小鼠造血系统的影响。我们将在脑卒中后不同时间点追踪HSC的增殖、交通和分化。我们将研究如何骨髓龛，调节HSC活性的微环境，中风后的变化。我们将进一步研究大脑和骨髓之间的长程信号，这些信号引发了所观察到的变化。我们将研究2个具体途径：a）增加交感神经信号传导，其通过小生境细胞上的β 3-肾上腺素受体作用以从骨髓中释放HSC，和B）从受损的脑组织释放HMGB1，因为这种alarmin可能作为toll样受体配体直接作用于HSC以增加增殖。在系列成像试验中，我们将检验抑制交感神经和HMGB1信号传导减少脑和动脉粥样硬化斑块中中风后炎症的假设。通过这样做，我们希望了解中风如何调节和动员骨髓造血细胞，以及这些过程对外周组织炎症，病变成熟，动脉粥样硬化形成和中风复发风险的贡献。这项拟议的研究通过调查中风后的神经免疫界面，弥合了神经科学，免疫学和造血干细胞生物学领域之间的重要知识差距，并汇集了两个具有互补专业知识的小组（Nazodorf，Moskowitz）。

DESCRIPTION (provided by applicant): The bone marrow has recently been implicated as a critical responder following stroke. As the site of hematopoiesis, it produces leukocytes that i) can enhance tissue injury or healing in the brain lesion and ii) sustain inflammation in atherosclerotic plaque triggering recurrent stroke. At the same time, leukocytes protect against infection. Clinical stroke data show increased circulating monocyte and neutrophil levels, indicating activation of innate immunity. Stroke patients are at higher risk for recurrent ischemic events (e.g., recurrent stroke) within months of the initial event, potentially due to stroke-associated acceleration of vessel wall inflammation and atherogenesis. A high incidence of post-stroke pneumonia is accompanied by decreased lymphocyte counts, indicating suppression of adaptive immunity. Our preliminary data show that the increased supply of innate immune cells after stroke enhances atherosclerosis in mice with hyperlipidemia (Nature 2012). The mechanism is currently unclear; however, new data obtained for this revised application show a vigorous increase of leukocyte production in the bone marrow after stroke. We thus propose testing the overarching hypothesis that there is important crosstalk between the ischemic brain and the hematopoietic system during the evolution of injury and repair. We hypothesize that ischemic brain injury activates hematopoietic stem cells (HSC) in the bone marrow and introduces a hematopoietic bias towards the myeloid cell lineage. Increased progenitor proliferation, we hypothesize, will lead to neutrophilia and monocytosis. Based on preliminary data and evidence in the literature, we hypothesize that these cells modulate the inflammatory response within the ischemic brain lesion and increase inflammation in atherosclerotic plaques. We propose to study the impact of ischemic stroke on the hematopoietic system in mice. We will follow proliferation, traffic and differentiation of HSC at different time points after stroke. We will investigate how the bone marrow niche, the microenvironment regulating HSC activity, changes after stroke. We will further investigate long-range signals between the brain and the bone marrow that instigate the observed changes. We will study 2 concrete pathways: a) increased sympathetic nervous signaling, which acts through �3-adrenoreceptors on niche cells to liberate HSC from the bone marrow, and b) HMGB1 released from damaged brain tissue, because this alarmin may act directly on HSC as a toll like receptor ligand to increase proliferation. In serial imaging trials, we will test the hypothesis tht inhibiting sympathetic nervous and HMGB1 signaling decreases post-stroke inflammation in the brain and in atherosclerotic plaque. By so doing, we hope to understand how stroke modulates and mobilizes bone marrow hematopoietic cells, and the contribution of these processes to peripheral tissue inflammation, lesion maturation, atherogenesis, and the risk of stroke recurrence. The proposed research bridges an important intellectual gap between the fields of neuroscience, immunology and hematopoietic stem cell biology by investigating the neuro-immunological interface after stroke, and brings together two groups with complimentary expertise (Nahrendorf, Moskowitz).