Complement protection and anaphylatoxins in neuroinflammation

中枢神经系统的炎症通常伴随着补体的激活和 补体系统与多种疾病有关，如阿尔茨海默病、肌营养不良 侧索硬化症和多发性硬化症。我们使用了铜试剂脱髓鞘-再髓鞘模型。 这表明补体在脱髓鞘过程中是一个负面因素，尽管缺乏完整的 补体系统显著延缓了再髓鞘形成。此外，该基因的表达也减少。 保护性Crry蛋白，提示对补体激活的易感性增加。为了支持这一想法， 中枢神经系统特异的可溶性Crry蛋白完全抑制脱髓鞘。这些结果表明，补体 即使在没有抗体参与的中枢神经系统疾病中也是活跃的(就像在Cuprizone模型中的情况)。在……里面 为了进一步阐明补体在神经炎症中的作用，我们建议进行以下测试 假设：(1)过敏性毒素蛋白的产生在脱髓鞘中起关键作用，但也是 对髓鞘再生很重要。C3a和C5a都是在补体激活过程中产生的，但它非常 很难分析这些蛋白质的作用，无论是单独的还是组合的。我们创作了一部小说 腺病毒构建和我们有这些蛋白质受体的基因缺失的小鼠，我们 可以用来检验我们的假设。(2)Crry表达的丧失在老茧体内创造了一个环境 这有助于补体的激活。我们的初步数据显示，CRY蛋白在 经铜酮处理的小鼠和中枢神经系统产生的可溶性Crry蛋白可防止脱髓鞘。这些数据 表明初级脱髓鞘是可以预防的，但对重新髓鞘形成的影响尚不清楚。我们会 使用腺病毒递送的可溶性Crry蛋白来测试该蛋白改变局部脱髓鞘的能力 并在这个系统中重新髓鞘形成。我们的研究将开始揭示不同的补体蛋白 在中枢神经系统中相互作用，调节不同的效应器功能。这些信息对于理解 补体如何以及何时可能成为中枢神经系统疾病的候选治疗靶点。

Inflammation in the central nervous system is often accompanied by complement activation and the complement system has been implicated in diverse disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We have utilized the cuprizone model of demyelination-remyelination and here show that complement is a negative factor during demyelination, however lack of an intact complement system significantly delays remyelination. In addition, there is decreased expression of the protective Crry protein, suggesting increased susceptiblity to complement activation. In support of this idea, CNS-specific soluble Crry protein completely inhibits demyelination. These results indicate that complement is active even in CNS diseases without antibody involvement (as is the case in the cuprizone model). In order to further delineate the role of complement in neuroinflammation we propose to test the following hypotheses: (1) The production of anaphylatoxin proteins plays a key role in demyelination, yet are also important for remyelination. Both C3a and C5a are produced during complement activation, yet it is very difficult to dissect the roles of these proteins, either alone or in combination. We have generated novel adenoviral constructs and we have mice with genetic deletions in the receptors for these proteins that we can use to test our hypothesis. (2) Loss of Crry expression creates an environment in the corpus callosum that facilitates complement activation. Our preliminary data have shown significant loss of Crry protein in cuprizone-treated mice and CNS production of soluble Crry protein prevents demyelination. These data show that primary demyelination can be prevented, but the effect on remyelination is yet unknown. We will use adenovirally delivered soluble Crry protein to test the ability of the protein to alter local demyelination and remyelination in this system. Our studies will begin to uncover how different complement proteins interact in the CNS to mediate diverse effector functions. This information will be critical for understanding how and when complement might be a candidate therapeutic target in CNS disease.