Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia

调节中风后炎症反应以改善脑缺血模型的结果

• 批准号: 10162676
• 负责人: Katrin I. Andreasson
• 金额: $ 48.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162676
• 关键词: Ablation; Adaptor Signaling Protein; Alzheimer' s disease risk; Amplifiers; Anti-Inflammatory Agents; Area; B-Lymphocytes; Brain; Brain Injuries; Cause of Death; Cell Lineage; Cells; Cerebral Ischemia; Colitis; Data; Dendritic Cells; Dinoprostone; Effectiveness; Equilibrium; Evolution; Family member; Gender; Immune; Immune response; Immune signaling; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Intervention; Intestines; Ischemia; Lead; Ligands; Membrane; Microglia; Modeling; Mus; Myelogenous; Myeloid Cells; PTGS2 gene; Pathway interactions; Patients; Pattern recognition receptor; Peptides; Peripheral; Phagocytes; Pharmacology; Phase; Population; Process; Receptor Signaling; Recovery; Recovery of Function; Regulation; Research; Rodent Model; Sepsis; Signal Pathway; Signal Transduction; Stroke; Surface; T-Lymphocyte; TREM2 gene; TYROBP gene; Testing; Therapeutic; Thrombolytic Therapy; Time; Up-Regulation; Validation; Variant; Work; aged; brain repair; chemokine; comorbidity; conditional knockout; disability; functional outcomes; genetic approach; immune function; improved; improved outcome; insight; macrophage; monocyte; mouse model; neuroprotection; neurotoxic; neutrophil; novel therapeutic intervention; post stroke; protective effect; receptor; recruit; response; stroke outcome; stroke recovery; transcriptomics

Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia ABSTRACT inflammatory responses. Stroke is a multiphasic process, with an initial ischemic phase followed by secondary progression of injury from Following ischemia, microglia and macrophages accumulate in the ischemic area and produce inflammatory mediators and chemokines that initially recruit peripheral macrophages, neutrophils, dendritic cells, and later T and B cells. This post-stroke inflammatory response is both beneficial and injurious, as multiple and simultaneous immune pathways in distinct immune cell populations generate both beneficial and maladaptive immune responses. Because the time window of intervention of thrombolytic strategies is limited after onset of ischemia, and because attempts at neuroprotection after stroke have not shown positive results, the post-stroke inflammatory response represents an attractive target for intervention to reduce brain injury and accelerate functional recovery. The identification of specific immune pathways activated after stroke that could be modulated therefore represents an opportunity to improve and accelerate recovery after stroke. In previous studies, we have focused on the beneficial effects of inhibiting COX-2/PGE2 inflammatory signaling through the myeloid PGE2 EP2 receptor. In these studies, we identified Triggering Receptor Expressed on Myeloid cells-1, or TREM1, as highly regulated by inflammatory PGE2 EP2 signaling. TREM1 is an inflammatory membrane receptor that is expressed only on myeloid lineage cells and is unique in its function as an amplifier of maladaptive inflammatory responses. Our preliminary data suggest that this immune signaling cascade enhances innate immune responses after cerebral ischemia days after stroke. Using a combination of pharmacological and conditional knockout strategies to isolate the contribution of peripheral immune cells to stroke, we propose to identify the mechanisms of action of TREM1 signaling after stroke and test the hypothesis that inhibition of this pathway in the days after stroke will enhance brain repair and accelerate recovery.

调节势后炎症反应以改善脑缺血模型的预后 抽象的 炎症反应。 中风是一个多相过程，其初始缺血阶段，然后是次要损伤的次要进展。 以下缺血，小胶质细胞和巨噬细胞在缺血区域积聚 产生炎症介质和趋化因子，最初募集外周巨噬细胞，中性粒细胞， 树突状细胞，后来的T和B细胞。这种中风后炎症反应既有益又有害， 由于多种和同时的免疫途径在不同的免疫细胞种群中产生两者有益 和适应不良的免疫反应。因为溶栓策略的干预时间窗口是 缺血发作后有限，并且因为中风后的神经保护尝试未显示阳性 结果，中风后炎症反应代表了减少大脑的有吸引力的目标 伤害并加速功能恢复。识别中风后激活的特定免疫途径 因此，可以调制这是一个机会，可以改善和加速中风后的恢复。 在先前的研究中，我们专注于抑制COX-2/PGE2炎症信号的有益作用 通过髓样PGE2 EP2受体。在这些研究中，我们确定了在 由炎症PGE2 EP2信号高度调节，髓样细胞1或TREM1。 TREM1是一个 仅在髓样谱系细胞上表达的炎性膜受体，其功能是独特的 作为适应不良炎症反应的放大器。我们的初步数据表明这种免疫力 信号级联在中风后几天后增强了脑缺血后的先天免疫反应。使用 药理学和有条件敲除策略的结合，以隔离周围的贡献 免疫细胞中风，我们建议确定中风后TREM1信号传导的作用机理 检验以下假设：中风后几天对该途径的抑制作用将增强脑修复和 加速恢复。