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

Caspase-8 在神经炎症、脱髓鞘和髓磷脂修复中的作用

基本信息

批准号：
9087353
负责人：
JIANRONG LI
金额：
$ 18.56万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087353
关键词：
Ablation Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Automobile Driving B cell differentiation Brain CASP8 gene CCL2 gene Caspase Cells Cessation of life Chronic Cuprizone Data Degenerative Disorder Demyelinating Diseases Demyelinations Exhibits Gatekeeping Genetic Genetic Polymorphism Health Heterogeneity Homeostasis Immune Immune response Immune system Immunity In Situ In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Intrinsic factor Link Lipopolysaccharides Macrophage Activation Mediating Microglia Modeling Molecular Genetics Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myeloid Cells Natural regeneration Nerve Neuraxis Neurodegenerative Disorders Oligodendroglia Pathogenesis Pathway interactions Peripheral Phosphotransferases Play Process Production RIPK3 gene Recruitment Activity Regulation Rodent Role Signal Transduction Slice Sterility System T-Cell Activation T-Lymphocyte Tissues Toxin base central nervous system demyelinating disorder genetic approach immune function in vivo insight macrophage monocyte mouse model nervous system disorder neuroinflammation new therapeutic target novel pathogen remyelination repaired response

项目摘要

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.

描述（由申请人提供）：小胶质细胞是中枢神经系统（CNS）中的驻留髓细胞，是中枢神经系统免疫的关键角色。小胶质细胞的过度和激活一直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，如何调节小胶质细胞激活/失活仍然知之甚少，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的关键调节剂。除了启动细胞凋亡炎症的外在途径的典型功能外，Caspase-8 还具有调节外周免疫细胞的激活、分化和存活的非细胞凋亡功能。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，表明 caspase-8 可能通过调节小胶质细胞的激活状态和存活来控制中枢神经系统免疫，我们的初步数据表明，包括小胶质细胞在内的骨髓细胞中条件性删除 Casp8 会导致神经炎症加剧。在多发性硬化症动物模型中，缺乏 caspase-8 的小胶质细胞在体外和培养的脑切片中表现出增强的促炎反应，我们发现 caspase-8 是一种限制小胶质细胞/巨噬细胞激活的看门人，小胶质细胞激活的失调可能会延续病理性中枢神经系统炎症反应并损害髓磷脂修复。在本提案中，我们将采用分子和遗传学方法来确定 caspase-8 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中枢神经系统脱髓鞘中的免疫功能。从这项研究中获得的见解不仅可能为多发性硬化症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影响，其中慢性激活的小胶质细胞/巨噬细胞是其病理特征的一部分。