A DAP12-Dependent Signal Promotes Pro-Inflammatory Polarization in Microglia Following Nerve Injury and Exacerbates Degeneration of Injured Neurons
A DAP12-Dependent Signal Promotes Pro-Inflammatory Polarization in Microglia Following Nerve Injury and Exacerbates Degeneration of Injured Neurons
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DOI：
10.1002/glia.22802
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发表时间：
2015-06-01
期刊：
影响因子：
6.2
通讯作者：
Kiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Kobayashi, Masaaki;Konishi, Hiroyuki;Kiyama, Hiroshi
在病理条件下，激活的小胶质细胞发挥矛盾的作用，并可能具有神经毒性或神经保护作用。然而，决定激活的小胶质细胞如何影响神经元细胞命运的信号在很大程度上仍然未知。在这里，我们证明了12 kDa的DNA激活蛋白（DAP 12），一种跨膜衔接蛋白，含有免疫受体酪氨酸为基础的激活基序，是神经损伤后小胶质细胞功能的关键调节因子。在小鼠舌下神经损伤模型中，神经损伤后小胶质细胞增加的持续时间在缺乏DAP 12的小鼠中变得更短，尽管小胶质细胞形态和总细胞数在神经损伤后的早期阶段没有受到显著影响。有趣的是，包括促炎细胞因子在内的M1表型标志物的表达在DAP 12缺陷型小胶质细胞中受到抑制。此外，在DAP 12缺陷小鼠中，轴突切断诱导的运动神经元死亡被显著预防。总的来说，轴突切断后DAP 12介导的小胶质细胞活化促进促炎反应，从而加速神经损伤诱导的神经元死亡，表明DAP 12是保护由小胶质细胞活化引起的神经元变性的潜在治疗靶点。GLIA 2015;63：1073-1082
Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX-activating protein of 12 kDa (DAP12), a transmembrane adaptor protein that contains an immunoreceptor tyrosine-based activation motif, is a critical regulator of microglial function after nerve injury. In a model of mouse hypoglossal nerve injury, the duration of microglial increase after nerve injury became shorter in mice lacking DAP12, although microglial morphology and total cell numbers were not significantly affected during early phase after nerve injury. Intriguingly, expressions of M1-phenotype markers including pro-inflammatory cytokines were suppressed in DAP12-deficient microglia. Furthermore, axotomy-induced motor neuron death was markedly prevented in DAP12-deficient mice. Collectively, DAP12-mediated microglial activation following axotomy promotes pro-inflammatory responses, and thereby accelerates nerve injury-induced neuron death, suggesting that DAP12 is a potential therapeutic target for the protection of neuronal degeneration caused by microglial activation. GLIA 2015;63:1073-1082