Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W 15th Street, Indianapolis, IN, 46202, USA.
Mol Neurodegener. 2017 Aug 2;12(1):56. doi: 10.1186/s13024-017-0197-5.
TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.
TREM2 变异被确定为阿尔茨海默病（AD）和其他神经退行性疾病（NDD）的风险因素。由于 TREM2 编码一种仅在免疫细胞上表达的受体，这些变异的鉴定明确表明免疫反应可以在 NDD 的发病机制中发挥积极作用。这些 TREM2 变异还赋予了发生阿尔茨海默病的最高风险，这是近二十年来确定的任何风险因素中最高的，这表明更多地了解 TREM2 功能可能为 NDD 病理学提供关键见解，并为新型免疫相关 NDD 生物标志物和治疗方法提供途径。为了了解免疫功能在疾病发病机制和进展中的作用，人们广泛研究了 TREM2 在 NDD 中的表达、信号转导和功能。我们全面回顾了我们目前对 TREM2 生物学的理解，包括对 TREM2 表达调控以及 TREM2 信号转导和功能在 NDD 中的新见解。虽然仍有许多悬而未决的问题，但目前的文献提供了一些问题的明确答案。虽然仍然经常引用促炎刺激物降低 TREM2 表达，但现在清楚的是，这在体外是正确的，但体内的炎症刺激物几乎普遍增加 TREM2 表达。同样，虽然 TREM2 功能通常被描述为促进抗炎表型，但超过一半的已发表研究表明 TREM2 具有促炎作用，这表明其在炎症中的作用要复杂得多。最后，将 TREM2 生物学的这些组成部分应用于讨论 TREM2 如何影响 NDD 病理学以及对这些发现如何应用于免疫导向的临床生物标志物和治疗方法的最新评估。
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