Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases.
Microglial TREM2/DAP12 Signaling: A Double-Edged Sword in Neural Diseases.
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DOI：
10.3389/fncel.2018.00206
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发表时间：
2018
影响因子：
5.3
通讯作者：
Kiyama H
中科院分区：
文献类型：
--
作者：
Konishi H;Kiyama H
小胶质细胞在神经元损伤后和神经退行性疾病中被激活，并引发中枢神经系统（CNS）中的神经炎症。小胶质细胞源性神经炎症对神经元既有有益的影响，也有有害的影响。由于小胶质细胞激活的时间和幅度被认为是神经元命运的关键决定因素，因此需要了解小胶质细胞激活的分子机制，以建立针对神经疾病的小胶质细胞靶向疗法。质膜受体作为小胶质细胞的激活剂发挥主要作用，在这篇综述中，我们专注于一个受体复合物，涉及触发受体表达的髓样细胞2（TREM 2）和DNAX激活蛋白的12 kDa（DAP 12），这两个基因的Nasu-Hakola病，骨囊肿痴呆症的致病基因。最近的转录组方法证明了TREM 2/DAP 12信号传导是将小胶质细胞从稳态转化为神经疾病相关状态的主要调节因子。此外，动物模型研究揭示了TREM 2/DAP 12在调节小胶质细胞活性（包括存活、吞噬作用和细胞因子产生）中的关键作用，不仅在阿尔茨海默病中，而且在其他神经疾病（如帕金森病、脱髓鞘疾病、缺血和外周神经损伤）中。有趣的是，虽然TREM 2/DAP 12介导的小胶质细胞活化对某些疾病（包括周围神经损伤）是有害的，但对其他疾病是有益的。由于激活的小胶质细胞在疾病模型中的作用不同，因此TREM 2/DAP 12信号传导可能导致不同疾病的不同结果。在这篇综述中，我们讨论了TREM 2/DAP 12在小胶质细胞中的作用及其对神经疾病的贡献的最新观点。
Microglia are activated after neuronal injury and in neurodegenerative diseases, and trigger neuroinflammation in the central nervous system (CNS). Microglia-derived neuroinflammation has both beneficial and detrimental effects on neurons. Because the timing and magnitude of microglial activation is thought to be a critical determinant of neuronal fate, understanding the molecular mechanisms underlying microglial activation is required to enable establishment of microglia-targeted therapies for neural diseases. Plasma membrane receptors play primary roles as activators of microglia and in this review, we focus on a receptor complex involving triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12), both of which are causative genes for Nasu-Hakola disease, a dementia with bone cysts. Recent transcriptome approaches demonstrated TREM2/DAP12 signaling as the principal regulator that transforms microglia from a homeostatic to a neural disease-associated state. Furthermore, animal model studies revealed critical roles for TREM2/DAP12 in the regulation of microglial activity, including survival, phagocytosis, and cytokine production, not only in Alzheimer's disease but also in other neural diseases, such as Parkinson's disease, demyelinating disease, ischemia, and peripheral nerve injury. Intriguingly, while TREM2/DAP12-mediated microglial activation is detrimental for some diseases, including peripheral nerve injury, it is beneficial for other diseases. As the role of activated microglia differs among disease models, TREM2/DAP12 signaling may result in different outcomes in different diseases. In this review we discuss recent perspectives on the role of TREM2/DAP12 in microglia and their contribution to neural diseases.
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影响因子：
5.1
作者：
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通讯作者：
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影响因子：
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作者：
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