Mechanisms of interleukin 6 signaling in astrocytes

摘要 神经炎症是中枢神经系统(CNS)在损伤后保护大脑的一种关键反应， 创伤和感染；然而，慢性神经炎被认为是 神经退行性疾病，如阿尔茨海默病、帕金森氏病和多发性硬化症。 炎症过程在免疫系统的细胞中得到了很好的描述，但对其如何发生却知之甚少。 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，已有报道称 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的介质。 由感染和损伤引起，在那里它们释放各种对招募新兵很重要的趋化因子和细胞因子 以及激活外周免疫细胞。这创建了一个重要的接口，在其中星形胶质细胞检测 在中枢神经系统内启动的病理可以反过来调节两个中枢神经系统的炎症进展 而且可能存在于系统免疫系统中。我们实验室正在进行的研究表明，老鼠摄入 与疾病相关的代谢性神经毒素鱼藤酮的促炎细胞因子水平升高 包括在脑提取液中观察到的白介素6(IL6)。IL-6是一种重要的炎症介质，其 与多种神经退行性疾病相关的水平升高。据报道，星形胶质细胞 在肿瘤坏死因子和白介素1b的作用下分泌白介素6；然而，我们还不知道 鱼藤酮暴露后观察星形胶质细胞是否是IL6的细胞来源。JAK/STAT信号 转导通路是由IL6激活的，最近有报道称它包含一个前馈的自分泌环路 在神经胶质瘤细胞中。如果在促炎症的星形胶质细胞中存在这样的机制，人们将非常感兴趣。 由于自发性神经炎被认为有助于正常衰老和糖尿病的进展 老年人的慢性神经功能障碍。培训方案的一个主要组成部分将是执行 分子生物学研究验证星形胶质细胞是疾病诱导的IL6的细胞来源的预测- 原代培养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 转导通路是由神经毒素激活的，一旦建立，这一通路可以在 停止暴露后，以IL6依赖的方式。在我们的第二个目标中，我们将使用组织学和 用生化技术确定IL6/JAK/STAT通路在小鼠体内最初是否被激活和持续 暴露于与疾病相关的杀虫剂鱼藤酮，并确定是否使用药物治疗 JAK/STAT的抑制剂可以使鱼藤酮暴露期间和之后小鼠的IL6水平恢复正常。理解 IL-6在星形胶质细胞和中枢神经系统细胞中诱导的基本细胞和分子机制 神经毒性应激可能确定检测和治疗神经炎症的新途径 与正常衰老和疾病有关。

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.