The Immunoinhibitory Role of CD200-CD200R1 Signaling in Experimental Stroke

CD200-CD200R1 信号在实验性卒中中的免疫抑制作用

• 批准号: 8733457
• 负责人: Rodney Ritzel
• 金额: $ 3.3万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2016-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733457
• 关键词: Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Back; Behavioral; Binding; Bone Marrow; Brain; Brain Injuries; CD 200; Cause of Death; Cell Surface Receptors; Cells; Cerebral Ischemia; Chimera organism; Clinical; Data; Development; Disease Progression; Economic Burden; Environment; Enzyme-Linked Immunosorbent Assay; Exclusion Criteria; FDA approved; Flow Cytometry; Functional disorder; Glycoproteins; Goals; Homeostasis; Hour; Immune; Immune system; Immunoglobulin G; Immunohistochemistry; Immunophenotyping; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemic Stroke; Knock-out; Knockout Mice; Lead; Leukocytes; Lifting; Ligands; Macrophage Activation; Mediating; Membrane; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Neurodegenerative Disorders; Neuronal Injury; Neurons; Outcome; Pathway interactions; Peripheral; Pharmaceutical Preparations; Play; Population; Predisposition; Process; Proteins; RNA Interference; Recovery; Regulation; Relative (related person); Reperfusion Therapy; Rest; Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Stroke; Structure; Therapeutic; Tissues; Transgenic Organisms; United States; Western Blotting; Work; cytokine; disability; global health; health economics; immunoregulation; improved; interest; macrophage; mortality; neuroinflammation; novel; protein expression; public health relevance; receptor; response to injury; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Emerging data suggests that stroke-induced inflammation significantly contributes to neuronal injury and clinical outcome. Local inflammatory responses following cerebral ischemia have highlighted a pivotal role for the innate immune system in the brain's response to injury, including the activation of microglia and macrophages. Cell-surface receptors (e.g., CD200R1) on microglia and other myeloid-derived cells directly interact with specific endogenous ligands (e.g ., CD200) expressed on neurons and act to suppress pro- inflammatory signaling by maintaining microglia in a "resting state". Normally these inhibitory mechanisms are required to keep the brain an immune-privileged site. When these interactions are broken, however, microglia can become disinhibited and enter a state of tonic activation, thereby exacerbating injury and worsening outcome. Thus, regulation of microglia after injury is crucial. Recent studies investigating the imbalance of CD200-CD200R1 signaling in models of neurodegenerative disease support the hypothesis that this interaction may also be disrupted following stroke. Preliminary data from our lab suggests that CD200 protein expression levels are decreased in the ischemic hemisphere early after experimental stroke, indicating that the inhibitory 'brake' on microglia is removed. Interestingly, we show a concurrent increase in CD200R1 protein levels after stroke, which coincided with an increased number of activated microglia and peripheral leukocyte recruitment. In this proposal we intend to elucidate the role of CD200-CD200R1 inhibitory signaling in stroke. In Aim 1 we will explore the functional consequences of these neuronal-glial interactions using conditional neuronal CD200 knockout and CD200R1 (global) knockout mice. Aim 2 will continue our mechanistic study of CD200R1- mediated inhibition by examining the local (microglia) and peripheral (leukocyte) contributions to stroke using CD200R1-/- bone marrow chimeras. Finally, Aim 3 will employ a small molecule CD200R1 agonist (CD200-Fc) for proof-of-principle of a therapeutic strategy to treat stroke. The overall goal of this proposal is to investigate the immunoregulatory mechanisms underlying microglia activation in brain injury and determine the efficacy of temporally suppressing microglia/myeloid activation to promote better outcomes and enhance recovery after stroke.

描述（由申请人提供）：新数据表明中风引起的炎症对神经元损伤和临床结果有显着影响。脑缺血后的局部炎症反应凸显了先天免疫系统在大脑对损伤的反应中的关键作用，包括小胶质细胞和巨噬细胞的激活。小胶质细胞和其他骨髓来源细胞上的细胞表面受体（例如 CD200R1）直接与神经元上表达的特定内源配体（例如 CD200）相互作用，并通过维持小胶质细胞处于“静息状态”来抑制促炎信号传导。通常，这些抑制机制需要使大脑保持免疫特权部位。然而，当这些相互作用被打破时，小胶质细胞就会变得不受抑制并进入强直激活状态，从而加剧损伤并使结果恶化。因此，损伤后小胶质细胞的调节至关重要。最近研究神经退行性疾病模型中 CD200-CD200R1 信号传导失衡的研究支持了这样的假设：这种相互作用也可能在中风后被破坏。我们实验室的初步数据表明，实验性中风后早期缺血半球的 CD200 蛋白表达水平下降，表明小胶质细胞的抑制“刹车”被消除。有趣的是，我们发现中风后 CD200R1 蛋白水平同时增加，这与激活的小胶质细胞和外周白细胞招募数量的增加同时发生。在本提案中，我们打算阐明 CD200-CD200R1 抑制信号在中风中的作用。在目标 1 中，我们将使用条件性神经元 CD200 敲除和 CD200R1（全局）敲除小鼠探索这些神经元-胶质细胞相互作用的功能后果。目标 2 将通过使用 CD200R1-/- 骨髓嵌合体检查局部（小胶质细胞）和外周（白细胞）对中风的贡献，继续我们对 CD200R1 介导的抑制的机制研究。最后，Aim 3 将采用小分子 CD200R1 激动剂 (CD200-Fc) 来验证中风治疗策略的原理。该提案的总体目标是研究脑损伤中小胶质细胞激活的免疫调节机制，并确定暂时抑制小胶质细胞/骨髓激活以促进更好的结果并促进中风后恢复的功效。