Mechanisms of interleukin 6 signaling in astrocytes

星形胶质细胞中白细胞介素 6 信号传导机制

• 批准号: 9331248
• 负责人: Eileen M Martinez
• 金额: $ 4.4万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331248
• 关键词: Abate; Alzheimer' s Disease; Astrocytes; Biochemical; Biomedical Research; Brain; Brain Diseases; Cells; Chronic; Coculture Techniques; Development; Disease; Distress; Elderly; Event; Excision; Exposure to; Functional disorder; Glioma; Histologic; Histological Techniques; Immune; Immune system; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Interleukins; Laboratories; Metabolic; Microglia; Molecular; Molecular Biology; Multiple Sclerosis; Mus; Nervous System Trauma; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurotoxins; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Peripheral; Pesticides; Pharmacology; Primary Cell Cultures; Process; Recruitment Activity; Reporting; Rotenone; Scientist; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Source; Stimulus; Stress; System; TNF gene; TNFRSF17 gene; Techniques; Testing; Toxic Environmental Substances; Toxin; Training; Training Programs; Trauma; autocrine; brain cell; career; chemokine; cytokine; design; experimental study; feeding; human disease; improved; inhibitor/antagonist; insight; interest; nervous system disorder; neuroinflammation; neurotoxic; normal aging; response; trafficking; tumor

Abstract Neuroinflammation is a key central nervous system (CNS) response that protects the brain following injury, trauma, and infection; however, chronic neuroinflammation is recognized as a pathologic manifestation of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Multiple Sclerosis. The inflammatory process is well characterized in cells of the immune system but less is known about how CNS cells can initiate inflammation. Neurons and glia are resident cells in the CNS that have been reported to secrete pro-inflammatory cytokines. Among CNS cells, astrocytes have emerged as mediators of inflammation resulting from infection and injury where they release various chemokines and cytokines important in recruiting and activating peripheral immune cells. This creates an important interface in which astrocytes detecting pathologies initiated within the CNS can then in turn modulate the progression of inflammation in both the CNS and potentially in the systemic immune system. Ongoing studies in our laboratory indicate that mice ingesting the disease-associated metabolic neurotoxin rotenone have elevated levels of the pro-inflammatory cytokines including interleukin 6 (IL6) observable in brain extracts. IL6 is an important inflammatory mediator whose levels are elevated in association with multiple neurodegenerative disorders. Astrocytes have been reported to secrete IL6 in response to tumor necrosis factor (TNF) and interleukin 1b (IL1b); however, we do not yet know whether astrocytes are the cellular origin of IL6 observed following rotenone exposure. The JAK/STAT signal transduction pathway is activated by IL6 and was recently reported to comprise a feed-forward autocrine loop in glial tumor cells. If such a mechanism existed in pro-inflammatory astrocytes it would be of great interest since self-perpetuating neuroinflammation is posited to contribute to normal aging and the progression of chronic neurologic disorders of the elderly. A major component of the training program will be the execution of molecular biology studies to test the prediction that astrocytes are the cellular origin of IL6 induced by disease- associated neurotoxin exposure in primary cultures. In these studies, we will determine if the JAK/STAT signal transduction pathway is activated by neurotoxins, and if once established, this pathway can be sustained in an IL6-dependent manner following cessation of exposure. In our second aim, we will use histologic and biochemical techniques to determine if the IL6/JAK/STAT pathway is activated and sustained in mice initially exposed to the disease-associated pesticide rotenone and determine if treatment with a pharmacologic inhibitor of JAK/STAT can normalize IL6 levels in mice during and following rotenone exposure. Understanding the basic cellular and molecular mechanisms of IL6 induction in astrocytes and in CNS cells subjected to neurotoxic stress may identify new pathways of interest for detecting and treating neuroinflammation occurring in association with normal aging and disease.

抽象的 神经炎症是一种关键的中枢神经系统 (CNS) 反应，可在受伤后保护大脑， 外伤、感染；然而，慢性神经炎症被认为是以下疾病的病理表现： 神经退行性疾病，例如阿尔茨海默病、帕金森病 (PD) 和多发性硬化症。 炎症过程在免疫系统细胞中得到了很好的表征，但对于如何进行炎症过程却知之甚少。 中枢神经系统细胞可以引发炎症。神经元和神经胶质细胞是中枢神经系统中的常驻细胞，据报道 分泌促炎细胞因子。在中枢神经系统细胞中，星形胶质细胞已成为炎症介质 由感染和损伤引起，它们释放各种对募集很重要的趋化因子和细胞因子 并激活外周免疫细胞。这创建了一个重要的接口，星形胶质细胞可以在其中检测 中枢神经系统内引发的病理学反过来又可以调节中枢神经系统炎症的进展 以及潜在的全身免疫系统。我们实验室正在进行的研究表明，小鼠摄入 与疾病相关的代谢神经毒素鱼藤酮具有升高的促炎细胞因子水平 包括在脑提取物中可观察到的白细胞介素 6 (IL6)。 IL6是一种重要的炎症介质 水平升高与多种神经退行性疾病相关。据报道星形胶质细胞 响应肿瘤坏死因子 (TNF) 和白细胞介素 1b (IL1b) 分泌 IL6；然而，我们还不知道 星形胶质细胞是否是鱼藤酮暴露后观察到的 IL6 的细胞来源。 JAK/STAT信号 转导途径由 IL6 激活，最近报道包含前馈自分泌环 在神经胶质瘤细胞中。如果这种机制存在于促炎性星形胶质细胞中，它将引起人们极大的兴趣 因为自我延续的神经炎症被认为有助于正常衰老和疾病进展 老年人的慢性神经系统疾病。培训计划的一个主要组成部分将是执行 分子生物学研究检验星形胶质细胞是疾病诱导的 IL6 细胞起源的预测 原代培养物中相关的神经毒素暴露。在这些研究中，我们将确定 JAK/STAT 信号是否 转导途径由神经毒素激活，一旦建立，该途径可以持续存在 停止暴露后出现 IL6 依赖性方式。在我们的第二个目标中，我们将使用组织学和 生化技术来确定 IL6/JAK/STAT 通路在小鼠体内最初是否被激活和维持 暴露于与疾病相关的杀虫剂鱼藤酮，并确定是否采用药物治疗 JAK/STAT 抑制剂可以使小鼠在鱼藤酮暴露期间和之后的 IL6 水平正常化。理解 星形胶质细胞和 CNS 细胞中 IL6 诱导的基本细胞和分子机制 神经毒性应激可能会发现检测和治疗发生的神经炎症的新途径 与正常衰老和疾病有关。