Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury
Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury
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DOI：
10.1523/jneurosci.2998-10.2010
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发表时间：
2010-10-13
影响因子：
5.3
通讯作者：
David, Samuel
中科院分区：
文献类型：
--
作者：
Ghasemlou, Nader;Lopez-Vales, Ruben;David, Samuel
炎症反应在脊髓损伤后继发性组织损伤和功能障碍中起重要作用。在这项工作中，我们通过对炎症反应高峰期的挫伤脊髓组织进行微阵列分析，确定了p38MAPK下游底物丝裂原活化蛋白激酶2(MAPKAPK2或MK2)是一个潜在的靶点。脊髓损伤后MK2表达和磷酸化增加，其中磷酸化MK2表达于小胶质细胞/巨噬细胞、神经元和星形胶质细胞。我们利用MK2(-/-)小鼠研究了MK2在脊髓挫伤中的作用。这些结果表明，与野生型对照组相比，MK2(-/-)小鼠的运动恢复能力显著提高。MK2(-/-)小鼠损伤部位前角尾侧5-羟色胺能纤维减少，神经元和髓鞘丢失减少。我们还发现MK2(-/-)和野生型小鼠脊髓损伤后基质金属蛋白酶-2和9的表达存在差异。在MK2(-/-)小鼠损伤脊髓中，促炎症细胞因子和蛋白亚硝化的表达也明显减少。我们先前的工作表明，缺乏MK2的巨噬细胞具有抗炎表型。我们现在发现，两个品系的小鼠损伤脊髓中的巨噬细胞数量没有差异，吞噬能力几乎没有差异，这表明缺乏MK2的巨噬细胞具有有益的表型。这些发现表明，缺少MK2可以减少脊髓损伤后的组织损伤，促进运动恢复。因此，MK2可能是治疗急性脊髓损伤的有用靶点。
The inflammatory response contributes importantly to secondary tissue damage and functional deficits after spinal cord injury (SCI). In this work, we identified mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of p38 MAPK, as a potential target using microarray analysis of contused spinal cord tissue taken at the peak of the inflammatory response. There was increased expression and phosphorylation of MK2 after SCI, with phospho-MK2 expressed in microglia/macrophages, neurons and astrocytes. We examined the role of MK2 in spinal cord contusion injury using MK2(-/-) mice. These results show that locomotor recovery was significantly improved in MK2(-/-) mice, compared with wild-type controls. MK2(-/-) mice showed reduced neuron and myelin loss, and increased sparing of serotonergic fibers in the ventral horn caudal to the injury site. We also found differential expression of matrix metalloproteinase-2 and 9 in MK2(-/-) and wild-type mice after SCI. Significant reduction was also seen in the expression of proinflammatory cytokines and protein nitrosylation in the injured spinal cord of MK2(-/-) mice. Our previous work has shown that macrophages lacking MK2 have an anti-inflammatory phenotype. We now show that there is no difference in the number of macrophages in the injured spinal cord between the two mouse strains and little if any difference in their phagocytic capacity, suggesting that macrophages lacking MK2 have a beneficial phenotype. These findings suggest that a lack of MK2 can reduce tissue damage after SCI and improve locomotor recovery. MK2 may therefore be a useful target to treat acute SCI.