Inflammatory mechanisms in cerebral ischemia

描述（由申请人提供）：中风是一种重要的神经系统疾病，很少有有效的治疗方法。了解脑卒中病理生理机制有助于确定合适的治疗方法。中风后的炎症现在被认为至少急性地增强了缺血性损伤，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 （TREM2）是近年来发现的一种参与先天免疫系统的受体。TREM2可以结合细菌和真核细胞，以及受损的神经元。TREM2也在小胶质细胞上表达，似乎可以促进受损神经元的吞噬。我们初步发现脑缺血后TREM2在小胶质细胞上的表达上调，其配体存在于神经元和星形胶质细胞上。TREM2似乎还具有抗炎特性，这可能限制中风的一些破坏性影响。我们认为TREM2通过促进缺血脑细胞的吞噬和降低免疫分子的表达来限制脑卒中损伤。在Aim 1中，我们将确定TREM2缺乏是否会导致实验性卒中和缺血样损伤后的损伤恶化，以及TREM2信号传导是否在缺血组织中发生。在Aim 2中，我们将确定TREM2是否以及如何参与介导小胶质细胞功能，如在缺血样损伤后吞噬受损神经元。通过体外缺血样损伤模型，我们将确定TREM2是否参与损伤神经元的吞噬，以及TREM2敲除或抑制是否会阻止这一过程。在Aim 3中，我们将利用脑卒中的骨髓嵌合体模型来确定TREM2功能对脑驻留（小胶质细胞）或循环（巨噬细胞）骨髓细胞的贡献。我们的总体假设是，attrem2对于受损脑细胞的吞噬是必不可少的，而受损组织的清除对于改善中风的预后是必不可少的。我们希望我们的研究将建立在我们对缺血炎症性脑反应的重要性的认识之上。

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.