Dynamic interactions between ischemic stroke, immunity and the bone marrow

缺血性中风、免疫和骨髓之间的动态相互作用

• 批准号: 8754405
• 负责人: Michael A. Moskowitz
• 金额: $ 63.07万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754405
• 关键词: Acceleration; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Bone Marrow; Brain; Bromodeoxyuridine; CXCL12 gene; Cathepsins; Cell Count; Cell Lineage; Cell Proliferation; Cells; Clinical; Commit; Data; Event; Evolution; HMGB1 gene; Healed; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hyperlipidemia; Image; Immune; Immunity; Immunology; Incidence; Infection; Inflammation; Inflammatory Response; Injury; Interdisciplinary Study; Ischemic Brain Injury; Ischemic Stroke; Lead; Lesion; Leukocytes; Ligands; Literature; Lymphocyte; Lymphocyte Count; Lymphoid; Measures; Mesenchymal Stem Cells; Metalloproteases; Middle Cerebral Artery Occlusion; Molecular; Molecular Biology; Molecular Immunology; Monocytosis; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Nature; Neurosciences; Neutrophilia; Pathway interactions; Patients; Peripheral; Pneumonia; Process; Production; Recurrence; Regulation; Research; Risk; Signal Transduction; Site; Stem cells; Stroke; Testing; Time; Tissues; Toll-like receptors; adaptive immunity; atherogenesis; base; brain tissue; healing; high risk; in vivo; injury and repair; monocyte; neutralizing antibody; neutrophil; post stroke; progenitor; programs; public health relevance; stem cell biology; tomography; trafficking; transcription factor

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).

描述(申请人提供)：骨髓最近被认为是中风后的关键应答者。作为造血点，它产生的白细胞可以促进脑部病变的组织损伤或愈合，以及维持动脉粥样硬化斑块的炎症，从而引发复发的中风。同时，白细胞还能保护人体免受感染。临床中风数据显示循环中单核细胞和中性粒细胞水平升高，表明天然免疫被激活。中风患者再发脑缺血的风险更高 在最初事件发生后的几个月内发生的事件(例如，复发性中风)，可能是由于中风相关的血管壁炎症和动脉粥样硬化的加速所致。中风后肺炎的高发病率伴随着淋巴细胞计数的下降，这表明适应性免疫受到抑制。我们的初步数据显示，中风后天然免疫细胞供应的增加加剧了高脂血症小鼠的动脉粥样硬化(自然，2012)。其机制目前尚不清楚；然而，为这一修订后的应用获得的新数据显示，中风后骨髓中白细胞的产生显著增加。因此，我们建议检验最重要的假设，即在损伤和修复的进化过程中，缺血脑和造血系统之间存在重要的串扰。我们假设缺血性脑损伤激活了骨髓中的造血干细胞(HSC)，并引入了对髓系细胞谱系的造血学偏向。我们假设，祖细胞增殖增加会导致中性粒细胞增多和单核细胞增多。根据初步数据和文献中的证据，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反应。我们建议研究缺血性卒中对小鼠造血系统的影响。观察卒中后不同时间点HSC的增殖、交通及分化情况。我们将研究中风后调节HSC活性的微环境--骨髓生态位的变化。我们将进一步研究引发观察到的变化的大脑和骨髓之间的远程信号。我们将研究两个具体的途径：a)增加交感神经信号，通过壁龛细胞上的3-肾上腺素受体从骨髓中释放HSC，以及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，促进HSC的增殖。在一系列成像试验中，我们将验证抑制交感神经和HMGB1信号可以减少中风后大脑和动脉粥样硬化斑块中炎症的假设。通过这样做，我们希望了解中风是如何调节和动员骨髓造血细胞的，以及这些过程对周围组织炎症、病变成熟、动脉粥样硬化和中风复发风险的贡献。这项拟议的研究通过研究中风后的神经免疫学接口，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智力鸿沟，并将具有互补专业知识的两个小组聚集在一起(纳伦多夫、莫斯科维茨)。