Huang DeRen, Tani Marie, Wang Jintang, Han Yulong, He Toby T, Weaver Jennifer, Charo Israel F, Tuohy Vincent K, Rollins Barrett J, Ransohoff Richard M
Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Neurosci. 2002 Dec 15;22(24):10633-42. doi: 10.1523/JNEUROSCI.22-24-10633.2002.
In this report we describe pertussis toxin-induced reversible encephalopathy dependent on monocyte chemoattractant protein-1 (MCP-1) overexpression (PREMO), a novel animal model that exhibits features of human encephalopathic complications of inflammatory disorders such as viral meningoencephalitis and Lyme neuroborreliosis as well as the mild toxic encephalopathy that commonly precedes relapses of multiple sclerosis (MS). Overexpression of the mouse MCP-1 gene product (classically termed JE) in astrocytes, the major physiological CNS cellular source of MCP-1, failed to induce neurological impairment. Unexpectedly, transgenic (tg) mice overexpressing MCP-1 at a high level (MCP-1(hi)) manifested transient, severe encephalopathy with high mortality after injections of pertussis toxin (PTx) plus complete Freund's adjuvant (CFA). Surviving mice showed markedly improved function and did not relapse during a prolonged period of observation. Tg mice that expressed lower levels of MCP-1 were affected minimally after CFA/PTx injections, and tg expression of other chemokines failed to elicit this disorder. The disorder was significantly milder in mice lacking T-cells, which therefore play a deleterious role in this encephalopathic process. Disruption of CC chemokine receptor 2 (CCR2) abolished both CNS inflammation and encephalopathy, identifying CCR2 as a relevant receptor for this disorder. Proinflammatory and type 1 cytokines including TNF-alpha, IL-1beta, IFN-gamma, IL-2, RANTES, and IP-10 were elevated in CNS tissues from mice with PREMO. These studies characterize a novel model of reversible inflammatory encephalopathy that is dependent on both genetic and environmental factors.
在本报告中，我们描述了百日咳毒素诱导的依赖单核细胞趋化蛋白-1（MCP-1）过表达的可逆性脑病（PREMO），这是一种新型动物模型，其展现出人类炎性疾病如病毒性脑膜脑炎和莱姆神经疏螺旋体病的脑病并发症以及多发性硬化症（MS）复发前常见的轻度中毒性脑病的特征。在星形胶质细胞（MCP-1主要的生理性中枢神经系统细胞来源）中过表达小鼠MCP-1基因产物（经典地称为JE）未能诱导神经功能损害。出乎意料的是，高水平过表达MCP-1的转基因（tg）小鼠在注射百日咳毒素（PTx）加完全弗氏佐剂（CFA）后出现短暂的严重脑病且死亡率高。存活的小鼠功能显著改善，并且在长时间观察期间未复发。表达较低水平MCP-1的tg小鼠在注射CFA/PTx后受到的影响最小，并且其他趋化因子的tg表达未能引发这种疾病。在缺乏T细胞的小鼠中，该疾病明显较轻，因此T细胞在这种脑病过程中起有害作用。破坏CC趋化因子受体2（CCR2）消除了中枢神经系统炎症和脑病，确定CCR2是该疾病的相关受体。包括TNF-α、IL-1β、IFN-γ、IL-2、RANTES和IP-10在内的促炎细胞因子和1型细胞因子在患有PREMO的小鼠的中枢神经系统组织中升高。这些研究描述了一种依赖遗传和环境因素的可逆性炎性脑病的新型模型。
