Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules
Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules
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DOI：
10.1016/s0169-328x(02)00158-4
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发表时间：
2002-06-30
期刊：
影响因子：
--
通讯作者：
Berman, NEJ
中科院分区：
文献类型：
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作者：
Muessel, MJ;Klein, RM;Berman, NEJ
皮层损伤后丘脑神经元逆行变性和死亡的调控机制尚不清楚。然而，细胞逆行性死亡发生的延迟和观察到的形态学变化与细胞凋亡一致。我们之前的研究表明，单核细胞趋化蛋白-1 （MCP-1）是一种吸引单核细胞到损伤部位的β趋化因子，在视觉皮质病变后，在外侧膝状核中迅速特异性表达。为了确定MCP-1在逆行变性中的潜在作用，本研究检测了MCP-1 （MCP-1 KO或-/-）或其高亲和受体CCR2 （CCR2 KO或-/-）基因缺失对成年小鼠视觉皮层吸入性病变后丘脑小胶质细胞激活和神经元细胞死亡的影响。MCP-1基因的缺失延迟了小胶质细胞的激活，并短暂地改善了丘脑神经元的存活。与野生型小鼠相比，CCR2受体的缺失导致损伤后核小体碎片的凋亡显著增加，但没有改变神经元的存活，这表明受体敲除小鼠的胶质细胞凋亡增加。通过对Bcl-2、Bax、Fas、Fas配体（FasL）和活化caspase-3这些细胞因子可调节细胞凋亡的关键调控因子的研究，揭示了MCP-/-和CCR2（-/-）小鼠mRNA和蛋白水平的复杂变化。例如，在野生型小鼠中检测到Bcl-2蛋白，但在MCP-/-小鼠中未检测到。损伤后5天，MCP-/-小鼠的Caspase-3活性高于野生型和CCR2（-/-）小鼠。高水平的活化caspase-3与MCP-/-小鼠丘脑中延迟但快速的细胞死亡的开始相关。总之，我们的数据强烈表明MCP-1参与了早期小胶质细胞对轴切的反应，并且调节这种趋化因子可能为改善中枢神经系统损伤后的神经元存活提供一种新的策略。(C) 2002 Elsevier Science B.V.版权所有
The mechanisms regulating retrograde neuronal degeneration and subsequent death of thalamic neurons following cortical injury are not well understood. However, the delay in the onset of retrograde cell death and observed morphological changes are consistent with apoptosis. Our previous studies demonstrated that monocyte chemoattractant protein-1 (MCP-1), a beta-chemokine that attracts cells of monocytic origin to sites of injury, is rapidly and specifically expressed in the lateral geniculate nucleus following visual cortical lesions. To determine the potential role of MCP-1 in retrograde degeneration, the present study examined the effect of genetic deletion of MCP-1 (MCP-1 KO or -/-) or its high affinity receptor CCR2 (CCR2 KO or -/-) on thalamic microglial activation and neuronal cell death following aspiration lesions of the visual cortex in adult mice. Deletion of the MCP-1 gene delayed microglial activation and transiently improved the survival of thalamic neurons. Deletion of the CCR2 receptor resulted in a significant increase in apoptosis as measured by nucleosomal fragmentation after injury compared to wild-type mice, but did not alter neuron survival, suggesting that glial apoptosis is increased in the receptor knockout mice. Investigation of Bcl-2, Bax, Fas, Fas ligand (FasL) and activated caspase-3, key regulators of apoptosis that can be modulated by cytokines, revealed complex alterations of mRNA and protein levels in MCP-/- and CCR2(-/-) mice. As examples, Bcl-2 protein was detected in wild-type, but not in MCP-/- mice. Caspase-3 activity was higher in MCP-/- mice compared to wild-type and CCR2(-/-) mice at 5 days after injury. High levels of activated caspase-3 correlate with the beginning of a period of delayed, but rapid cell death in the thalami of MCP-/- mice. In summary, our data strongly suggest that MCP-1 is involved in early microglial response to axotomy and that modulation of this chemokine could provide a novel strategy for improved neuronal survival following injury to the central nervous system. (C) 2002 Elsevier Science B.V. All rights reserved.