Selective chemokine mRNA expression following brain injury
Selective chemokine mRNA expression following brain injury
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DOI：
10.1016/s0006-8993(97)01160-8
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发表时间：
1998-03-30
期刊：
影响因子：
2.9
通讯作者：
Klein, RM
中科院分区：
文献类型：
--
作者：
Hausmann, EHS;Berman, NEJ;Klein, RM
非神经元组织中的损伤刺激趋化因子表达，导致负责协调修复过程的炎性细胞的募集。参与指导大脑损伤修复的信号还不太清楚。我们假设脑损伤后，趋化因子表达并调节炎症细胞积聚的速率和模式。这两个趋化因子亚家族是α（alpha）-趋化因子和β（beta）趋化因子，α-趋化因子主要起中性粒细胞趋化剂的作用，β-趋化因子主要起单核细胞趋化剂的作用。我们评估了大脑皮质损伤后α和β趋化因子mRNA表达模式和白细胞积聚。皮质病变产生和不添加内毒素，大肠杆菌脂多糖（LPS），刺激细胞因子的表达。我们研究了β-趋化因子：单核细胞趋化蛋白的表达，（基因产物JE; MCP-1/JE）、巨噬细胞炎症蛋白-1 α和β（MIP-1 α和MIP-1 β）、活化后调节的正常T表达和分泌的趋化因子（RANTES）以及α-趋化因子：干扰素-γ诱导蛋白（IP-10）和N51/KC（KC; MIP-2的小鼠同源物）。通过北方分析在损伤后的不同时间点分析基因表达的变化。在相同的时间间隔通过免疫组织化学分析白细胞和巨噬细胞密度。皮质损伤/内毒素后所有趋化因子均升高。MCP-1和MIP-1 α在2 h升高，6 h达到峰值，MIP-1 β在6 h达到峰值，但下降速度快于MCP-1或MIP-1 α，IP-10在6 h达到峰值，下降速度最快。KC在LPS刺激后1h升高，6 h达高峰。RANTES在1 h升高，在6 ~ 18 h达到平台水平，然后下降。相比之下，无菌损伤产生的内毒素的情况下，只诱导β-趋化因子MCP-1的mRNA，其表达延迟相比，皮质损伤/内毒素组。早在1小时就存在趋化因子信息，表明这类分子的表达是创伤性脑损伤后修复过程中的早期反应。巨噬细胞/小胶质细胞的积累发生得更快，激活小胶质细胞进一步从病变边界，和更多的细胞积累在皮质损伤/内毒素比在无菌条件下产生的皮质病变。因此，在β-趋化因子表达和在损伤部位积累的β-趋化因子应答细胞（即小胶质细胞）的数量之间存在正相关性。这是第一个使用一组趋化因子探针和特异性巨噬细胞/小胶质细胞标记物来研究损伤后大脑体内激活的综合研究。我们的数据表明，大脑能够表达多种趋化因子基因后，适当的刺激（如LPS治疗）。小胶质细胞激活的梯度与物理损伤刺激从损伤部位扩散的趋化因子的释放一致。这些数据有力地表明，趋化因子在脑损伤后修复过程的启动中起作用。(C)1998年Elsevier Science B.V.
Injury in non-neuronal tissues stimulates chemokine expression leading to recruitment of inflammatory cells responsible for orchestration of repair processes. The signals involved in directing repair of damage to the brain are less well understood. We hypothesized that following brain injury, chemokines are expressed and regulate the rate and pattern of inflammatory cell accumulation. The two chemokine subfamilies are alpha(alpha)-chemokines, which primarily function as neutrophil chemoattractants, and the beta(beta)chemokines, which function primarily as monocyte chemoattractants. We assessed alpha and beta chemokine mRNA expression patterns and leukocyte accumulation following a cerebral cortical lesion. Cortical lesions were produced with and without addition of endotoxin, Escherichia coli lipopolysaccharide (LPS), which stimulates cytokine expression. We studied the expression of the beta-chemokines: monocyte chemoattractant protein (gene product JE; MCP-1/JE), macrophage inflammatory protein-1 alpha and beta (MIP-1 alpha and MIP-1 beta), and the regulated upon activation normal T expressed and secreted chemokine (RANTES) as well as the alpha-chemokines: interferon-gamma-inducible protein (IP-10) and N51/KC (KC; a murine homologue of MIP-2). Changes in gene expression were analyzed by northern analysis at different time points following injury. Leukocyte and macrophage densities were analyzed by immunohistochemistry at the same time intervals. All chemokines were elevated following cortical injury/endotoxin. MCP-1 and MIP-1 alpha were elevated at 2 h and peaked 6 h, MIP-1 beta peaked at 6 h, but declined more rapidly than MCP-1 or MIP-1 alpha, and IP-10 peaked at 6 h and showed the most rapid decline. KC was elevated at 1 h, and peaked at 6 h following LPS. RANTES was elevated at 1 h and achieved a plateau level between 6 and 18 h, then declined. In contrast, sterile injuries produced in the absence of endotoxin only induced the mRNA of the beta-chemokine MCP-1, and its expression was delayed compared to the cortical injury/endotoxin group. The presence of chemokine message as early as 1 h indicates that expression of this class of molecules is an early response in the repair process following traumatic brain injury. Macrophage/microglia accumulation occurred more rapidly, activated microglia further from the lesion border, and more cells accumulated in cortical injury/endotoxin than in cortical lesions produced under sterile conditions. Thus, there was a positive correlation between beta-chemokine expression and the number of beta-chemokine responsive cells (i.e. microglia) accumulating in injury sites. This is the first comprehensive study using a panel of chemokine probes and specific marcophage/microglial markers to study in vivo activation of the brain following injury. Our data show that the brain is capable of expression of multiple chemokine genes upon appropriate stimulation (e.g. LPS-treatment). The gradient of microglial activation is consistent with physical damage stimulating release of chemokines that diffuse from the injury site. These data strongly suggest that chemokines are instrumental in the initiation of repair processes following brain injury. (C) 1998 Elsevier Science B.V.