Role of Caspase-8 in Neuroinflammation, Demyelination and Myelin Repair

 描述(申请人提供)：小胶质细胞是中枢神经系统(CNS)中常驻的髓样细胞，是中枢神经系统免疫的关键分子。小胶质细胞的过度和持续激活与许多神经系统疾病有关，包括神经退行性疾病和多发性硬化症(MS)。然而，小胶质细胞的激活/失活是如何被调控的，目前还知之甚少。根据我们最近的发现，我们认为caspase-8是小胶质细胞激活和中枢神经系统炎症的关键调节剂。Caspase-8除了具有启动外源性细胞凋亡途径的典型功能外，还具有调控外周免疫细胞活化、分化和存活的非凋亡性功能。在 在中枢神经系统中，我们发现小胶质细胞是表达caspase-8的主要细胞，提示caspase-8可能通过调节小胶质细胞的激活状态和存活来调控中枢神经系统的免疫。我们的初步数据表明，在包括小胶质细胞在内的髓系细胞中有条件地删除Casp8会加剧MS动物模型的神经炎症，而在体外和培养的脑片中，Caspase-8缺陷的小胶质细胞表现出增强的促炎反应。我们假设caspase-8是限制小胶质细胞/巨噬细胞激活的守门人，小胶质细胞激活的失调可能使病理性的中枢神经系统炎症反应持续存在，并损害髓鞘修复。在这项提案中，我们将使用分子和遗传学方法来确定caspase-8在体外和体内调节小胶质细胞激活和炎症反应的机制。这项研究首次揭示了caspase-8在中枢神经系统脱髓鞘和再髓鞘形成中的免疫功能。这项研究不仅可能为MS的发病机制提供新的视角，而且对许多其他神经退行性疾病也有意义，在这些疾病中，慢性激活的小胶质细胞/巨噬细胞是病理特征的一部分。

 DESCRIPTION (provided by applicant): Microglia are the resident myeloid cells in the central nervous system (CNS) and the key player of CNS immunity. Excessive and persistent activation of microglia has been implicated in many neurological disorders including neurodegenerative diseases and multiple sclerosis (MS). However, how microglia activation/deactivation is regulated remains poorly understood. Based on our recent findings, we propose that caspase-8 is a key modulator for microglial cell activation and CNS inflammation. Besides its canonical function in initiating the extrinsic pathway of apoptosis, caspase-8 possesses non-apoptotic functions in regulating activation, differentiation and survival of peripheral immune cells. In the CNS, we found that microglia are the predominant cells expressing caspase-8, indicating that caspase-8 may control CNS immunity by regulating microglia activation status and survival. Our preliminary data demonstrate that conditional deletion of Casp8 in myeloid cells including microglia results in exacerbated neuroinflammation in animal models of MS, and that caspase-8-deficient microglia exhibit enhanced proinflammatory responses in vitro and in cultured brain slices. We hypothesize that caspase-8 is a gatekeeper that restricts microglia/macrophage activation and that dysregulation of microglial activation may perpetuate pathological CNS inflammatory responses and impair myelin repair. In this proposal, we will employ molecular and genetic approaches to determine the mechanism by which caspase-8 regulates microglial activation and inflammatory responses in vitro and in vivo. This study represents the first to unravel the previously unrecognized immune function of caspase-8 in CNS demyelination and remyelination. Insights gained from this study are likely to provide not only new perspectives for the pathogenesis of MS, but also have implications in many other neurodegenerative diseases where chronically activated microglia/macrophages are part of pathological features.