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

调节卒中后炎症反应以改善脑缺血模型的预后 摘要 炎症反应。 中风是一个多阶段的过程，最初的缺血阶段，其次是继发性进展的损伤， 缺血后，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，最初招募外周巨噬细胞、中性粒细胞， 树突状细胞，以及后来的T和B细胞。这种中风后的炎症反应既有益又有害， 由于不同免疫细胞群中的多种和同时的免疫途径产生有益的 和适应不良的免疫反应因为溶栓策略干预的时间窗是 缺血发作后有限，并且因为中风后神经保护的尝试没有显示出积极的作用， 结果，中风后炎症反应是一个有吸引力的干预目标，以减少脑 加速功能恢复。脑卒中后激活的特异性免疫通路的鉴定 因此，可以调节的脑电活动提供了改善和加速中风后恢复的机会。 在以前的研究中，我们关注的是抑制考克斯-2/PGE 2炎症信号的有益作用 通过骨髓PGE 2 EP 2受体。在这些研究中，我们确定了触发受体表达在 髓样细胞-1或TREM 1，受炎性PGE 2 EP 2信号高度调节。TREM 1是一种 一种仅在髓系细胞上表达且功能独特的炎性膜受体 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 信号级联增强脑缺血后先天免疫应答。使用 药理学和条件性敲除策略的组合以分离外周血淋巴细胞的贡献， 免疫细胞中风，我们建议确定中风后TREM 1信号传导的作用机制， 测试假设，即在中风后的几天内抑制这一通路将增强大脑修复， 加快复苏。

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.