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Dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and motor neuron loss in the spinal cord of ALS mouse model
Translational Neurodegeneration ( IF 10.8 ) Pub Date : 2018-12-21 , DOI: 10.1186/s40035-018-0138-4
Jingjing Zhang 1, 2, 3 , Yufei Liu 1, 2 , Xinyao Liu 1, 2 , Song Li 1, 2 , Cheng Cheng 1, 2 , Sheng Chen 4 , Weidong Le 1, 2
Affiliation  

Neuron-microglia communication plays a crucial role in the motor neurons (MNs) death in amyotrophic lateral sclerosis (ALS). Neurons can express chemokine (C-X3-C motif) ligand 1 (CX3CL1), which mediates microglial activation via interacting with its sole receptor CX3CR1 in microglia. In the present study, we aimed to investigate the dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and MNs loss in SOD1G93A mouse model of ALS. qPCR, western blot and immunofluorescent staining were used to examine the mRNA and protein levels and localization of CX3CL1/CX3CR1 in the anterior horn region of spinal cord in both SOD1G93A mice and their age-matched wild type (WT) littermates at 40, 60, 90 and 120 days of age. The M1/M2 microglial activation in the spinal cord tissues of SOD1G93A mice and WT mice were evaluated by immunofluorescent staining of M1/M2 markers and further confirmed by qPCR analysis of M1/M2-related cytokines. The immunofluorescent staining revealed that CX3CL1 was predominately expressed in MNs, while CX3CR1 was highly expressed in microglia in the anterior horn region of spinal cord. Compared with age-matched WT mice, CX3CL1 mRNA level was elevated at 40 days but decreased at 90 and 120 days in the anterior horn region of spinal cords in ALS mice. Consistently, CX3CR1 mRNA level was increased at 90 and 120 days. Western blot assay further confirmed the dynamic changes of CX3CL1/CX3CR1 axis in ALS mice. Additionally, the levels of M1/M2 markers of microglia and their related cytokines in the anterior horn region of spinal cord in ALS mice were increased at 90 and 120 days. Moreover, while M1-related cytokines in ALS mice were persistently increased at 120 days, the upregulated M2-related cytokines started to decline at 120 days, suggesting an altered microglial activation. Our data revealed the dynamic changes of CX3CL1/CX3CR1 axis and an imbalanced M1/M2 microglial activation during ALS pathological progression. These findings may help identify potential molecular targets for ALS therapy.

中文翻译:

ALS小鼠模型脊髓小胶质细胞激活和运动神经元丢失过程中CX3CL1/CX3CR1轴的动态变化

神经元-小胶质细胞通讯在肌萎缩侧索硬化症 (ALS) 中的运动神经元 (MNs) 死亡中起着至关重要的作用。神经元可以表达趋化因子(C-X3-C 基序)配体 1 (CX3CL1),它通过与小胶质细胞中的唯一受体 CX3CR1 相互作用来介导小胶质细胞活化。在本研究中,我们旨在研究 ALS SOD1G93A 小鼠模型中小胶质细胞激活和 MNs 丢失过程中 CX3CL1/CX3CR1 轴的动态变化。qPCR、蛋白质印迹和免疫荧光染色用于检查 SOD1G93A 小鼠及其年龄匹配的野生型 (WT) 同窝小鼠在 40、60、 90 天和 120 天。通过 M1/M2 标志物的免疫荧光染色评估 SOD1G93A 小鼠和 WT 小鼠脊髓组织中的 M1/M2 小胶质细胞活化,并通过 M1/M2 相关细胞因子的 qPCR 分析进一步证实。免疫荧光染色显示CX3CL1主要在MNs中表达,而CX3CR1在脊髓前角区的小胶质细胞中高表达。与年龄匹配的 WT 小鼠相比,ALS 小鼠脊髓前角区的 CX3CL1 mRNA 水平在 40 天时升高,但在 90 天和 120 天时降低。一致地,CX3CR1 mRNA 水平在 90 天和 120 天增加。Western印迹分析进一步证实了ALS小鼠中CX3CL1/CX3CR1轴的动态变化。此外,ALS小鼠脊髓前角区小胶质细胞M1/M2标志物及其相关细胞因子水平在90天和120天时升高。此外,虽然 ALS 小鼠中的 M1 相关细胞因子在 120 天时持续增加,但上调的 M2 相关细胞因子在 120 天时开始下降,这表明小胶质细胞活化发生了改变。我们的数据揭示了 ALS 病理进展过程中 CX3CL1/CX3CR1 轴的动态变化和不平衡的 M1/M2 小胶质细胞激活。这些发现可能有助于确定 ALS 治疗的潜在分子靶点。我们的数据揭示了 ALS 病理进展过程中 CX3CL1/CX3CR1 轴的动态变化和不平衡的 M1/M2 小胶质细胞激活。这些发现可能有助于确定 ALS 治疗的潜在分子靶点。我们的数据揭示了 ALS 病理进展过程中 CX3CL1/CX3CR1 轴的动态变化和不平衡的 M1/M2 小胶质细胞激活。这些发现可能有助于确定 ALS 治疗的潜在分子靶点。
更新日期:2018-12-21
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