The Role of Triggering Receptor Expressed on Myeloid Cells-2 (Trem2) on Microglia

描述（由申请人提供）：小胶质细胞被称为大脑的巨噬细胞，作为先天免疫系统的一部分，它们不断监测中枢神经系统（CMS）的完整性并对损伤做出快速反应。小胶质细胞可以启动炎症和抗炎免疫反应，但对激活小胶质细胞的机制和信号了解甚少。在小胶质细胞上仅鉴定了少数与细胞活化或抑制相关的受体。髓样细胞上表达的触发受体-2（TREM 2）和DAP 12是在小胶质细胞的细胞表面上表达的受体复合物，并且先前已被表征为骨髓衍生细胞（诸如巨噬细胞、未成熟树突细胞和小胶质细胞）上的免疫调节分子。TREM 2-DAP 12复合物对于预防一种称为Nasu-Hakola病的罕见神经退行性疾病至关重要，但刺激TREM 2的配体和/或细胞尚不清楚。有证据表明，TREM 2可能被来自凋亡神经元细胞的信号激活，凋亡神经元细胞诱导小胶质细胞的吞噬作用而不诱导炎症。我们的具体目标是证明TREM 2在小胶质细胞上与体外和体内神经元上表达的配体接合后的功能。我们的工作将探索TREM 2在神经退行性疾病帕金森病中的重要性，帕金森病是最常见的神经退行性疾病之一，过度的小胶质细胞炎症反应被认为是有害的。该项目的长期目标是阐明TREM 2在小胶质细胞中的作用，并了解该受体在神经炎症和神经变性过程中的重要性，改善人类健康。了解TREM 2的作用的意义可能适用于多种神经和免疫疾病。

DESCRIPTION (provided by applicant): Microglia are known as macrophages of the brain, and as part of the innate immune system they constantly monitor the integrity of the central nervous system (CMS) and respond quickly to insults. Microglia can initiate both inflammatory and anti-inflammatory immune responses, but the mechanisms and signals that activate microglia towards either state are poorly understood. Only a few receptors related to cellular activation or inhibition have been identified on microglia. Triggering receptor expressed on myeloid cells-2 (TREM2) and DAP12 are a receptor complex expressed on the cell surface of microglia, and has been previously characterized as an immunoregulatory molecule on myeloid-derived cells, such as macrophages, immature dendritic cells, and microglia. The TREM2-DAP12 complex is critical to prevent a rare neurodegenerative disease called Nasu-Hakola disease, but ligands and/or cells that stimulate TREM2 are unknown. There is evidence to suggest that TREM2 may be activated by signals from apoptotic neuronal cells that induce phagocytosis by microglia without inducing inflammation. Our specific aims are to demonstrate the function of TREM2 on microglia upon engagement with ligands expressed on neurons in vitro and in vivo. Our work will explore the importance of TREM2 during the neurodegenerative disease, Parkinson's disease, which is one of the most common neurodegenerative disorders where excessive microglial inflammatory responses are considered harmful. The long-term objectives of this project are to elucidate the role of TREM2 on microglia, and to understand the importance of this receptor during neuroinflammation and neurodegeneration, and improve human health. The significance of understanding the role of TREM2 may be applied to multiple neurological and immunological diseases.