Inflammatory mechanisms in cerebral ischemia

描述（由申请人提供）：中风是一种严重的神经系统疾病，几乎没有有效的治疗方法。了解中风病理生理学的机制可能有助于确定适当的治疗方法。目前认为卒中后炎症至少急性加重缺血性损伤，但在清除坏死碎片和启动再生过程中可能很重要。髓样细胞表达的触发受体-2（TREM 2）是最近发现的参与先天免疫系统的受体。TREM 2与细菌和真核细胞以及受损的神经元结合。TREM 2也在小胶质细胞上表达，在那里它似乎促进受损神经元的吞噬作用。我们初步发现脑缺血后小胶质细胞TREM 2表达上调，其配体存在于神经元和星形胶质细胞上。TREM 2似乎也具有抗炎特性，这可能会限制中风的一些破坏性影响。我们认为TREM 2通过促进缺血性脑细胞的吞噬作用和减少免疫分子表达来限制中风引起的损伤。在目标1中，我们将确定TREM 2缺乏是否导致实验性中风和缺血样损伤后的损伤恶化，以及TREM 2信号传导是否发生在缺血组织中。在目标2中，我们将确定TREM 2是否以及如何参与介导小胶质细胞功能，例如在缺血样损伤后吞噬受损神经元。使用缺血样损伤的体外模型，我们将确定TREM 2是否参与受损神经元的吞噬作用，以及TREM 2敲低或其抑制是否会阻止这一点。在目标3中，我们将通过利用中风的骨髓嵌合体模型来确定由于脑驻留（小胶质细胞）或循环（巨噬细胞）髓样细胞导致的TREM 2功能的贡献。我们的首要假设是TREM 2对于吞噬受损脑细胞是必不可少的，并且清除受损组织对于改善中风的结果是必不可少的。我们希望我们的研究将建立在我们对缺血性脑炎症反应的重要性的认识基础上。 公共卫生相关性：中风是一种严重的神经系统疾病，几乎没有有效的治疗方法。中风后的炎症被认为是由于非特异性免疫反应导致邻近健康脑组织损伤而增加损伤。然而，炎症在去除死亡组织和帮助恢复方面也可能很重要。这是如何发生的还不清楚，但一种新的受体TREM 2可能在这个过程中很重要。TREM 2似乎可以减少炎症蛋白，但也可以促进吞噬作用，即免疫细胞去除细胞碎片的过程。了解TREM 2如何影响中风期间的炎症可能会导致确定适当的治疗方法。

DESCRIPTION (provided by applicant): Stroke is a significant neurological illness with few effective treatments. Understanding mechanisms underlying stroke pathophysiology may help identify appropriate treatments. Inflammation following stroke is now recognized to potentiate ischemic injury at least acutely, but may be important in clearing necrotic debris and initiating regenerative processes. Triggering receptor expressed by myeloid cells-2 (TREM2) is a recently discovered receptor involved in the innate immune system. TREM2 binds to both bacteria and eukaryotic cells, as well as injured neurons. TREM2 is also expressed on microglia, where it appears to promote the phagocytosis of injured neurons. We have preliminarily found that expression of TREM2 on microglia is upregulated following brain ischemia, and its ligands are present on neurons and astrocytes. TREM2 also appears to have anti- inflammatory properties, which could limit some of the damaging effects of stroke. We propose that TREM2 limits injury due to stroke by promoting the phagocytosis of ischemic brain cells and reduces immune molecule expression. In Aim 1, we will determine whether TREM2 deficiency leads to worsened injury following experimental stroke and ischemia-like insults, and whether TREM2 signaling occurs in ischemic tissue. In Aim 2, we will determine whether and how TREM2 is involved in mediating microglial functions such as phagocytosing injured neurons following ischemia like insults. Using in vitro models of ischemia-like injury, we will determine whether TREM2 is involved in the phagocytosis of injured neurons, and whether TREM2 knockdown or its inhibition will prevent this. In Aim 3, we will determine the contributions of TREM2 functions due to brain resident (microglia) or circulating (macrophages) myeloid cells by utilizing a bone marrow chimera model of stroke. Our overarching hypothesis is thatTREM2 is essential for phagocytosis of injured brain cells, and the clearance of injured tissue is essential to improved outcome from stroke. We hope that our studies will build on our knowledge of the significance of the inflammatory brain response to ischemia. PUBLIC HEALTH RELEVANCE: Stroke is a significant neurological illness with few effective treatments. Inflammation following stroke is thought to increase damage due to non specific immune reactions causing injury to adjacent healthy brain tissue. However, inflammation may also be important in removing dead tissue and aiding in recovery. How this occurs is not well known, but a new receptor, TREM2 may be important in this process. TREM2 seems to reduce inflammatory proteins, but also encourage phagocytosis, or the process where immune cells remove cellular debris. Understanding how TREM2 affects inflammation during stroke could lead to the identification of appropriate treatments.