The role of glucocorticoid signaling in immune cells during excitotoxicity.

兴奋性毒性期间糖皮质激素信号在免疫细胞中的作用。

• 批准号: 7675569
• 负责人: Shawn Sorrells
• 金额: $ 3.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675569
• 关键词: Acute; Adrenal Glands; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Cells; Cessation of life; Chronic; Cytokine Signaling; Endotoxins; Exposure to; Glucocorticoids; Hormones; Immune; Immune Targeting; Immune response; Immunosuppressive Agents; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Kainic Acid; Knock-out; Knockout Mice; Leukocytes; Measures; Microglia; Mineralocorticoid Receptor; Mus; Neurons; Nuclear Hormone Receptors; Peripheral; Production; Property; Rattus; Receptor Signaling; Role; Signal Transduction; Site; Stress; TNF gene; Testing; Tissues; Wild Type Mouse; Work; base; cell type; central nervous system injury; cytokine; design; excitotoxicity; granulocyte; injured; macrophage; receptor; receptor-mediated signaling; research study; transcription factor

DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are hormones released from the adrenal glands during stress and are well known for their potent and pleiotropic anti-inflammatory effects. In the injured CNS, their anti-inflammatory properties could be beneficial in cases where excessive inflammation imperils neuron survival. It is therefore important to understand specifically how GCs affect the immune response in the brain, especially given emerging evidence that under some circumstances GCs do not decrease inflammation and can even augment aspects of the immune response during CMS injury. It is well established that acute GC exposure can augment localized inflammatory responses while longer-term GC exposure is immunosuppressive. However, chronic GC exposure was recently found to increase CMS infiltration of macrophages, granulocytes, and microglia to excitotoxic injury accompanied by elevated levels of the pro-inflammatory cytokines IL-1(i, TNF-a, and IL-6. Chronic GC exposure was also found to augment CMS signaling of these cytokines and the pro-inflammatory transcription factor NFicB from peripheral exposure to endotoxin. Given their well-known anti-inflammatory properties, it is surprising that GCs do not blunt, but instead increase these inflammatory responses. Based on these findings, it is possible that chronic exposure to GCs augments the inflammatory response in the injured CMS. Chronic GC exposure could elevate CNS inflammation by stimulating any of the GC receptor subtypes in any of the cells present in the CNS. Two different nuclear hormone receptors for GCs exist, namely the GC receptor (GR) and the mineralocorticoid receptor (MR). A GR antagonist blocks the GC-augmented CNS inflammation, implicating the GR in this phenomenon; however it is unclear which cell type(s) are acted on by GCs to cause these pro-inflammatory effects. The most likely neuro-immune targets of GCs are the resident microglia and the peripheral leukocytes that extravasate to the site of injury. Both of these cell types express GR and are instrumental in orchestrating immune responses to acute injury. This proposal is designed to measure immune cell-specific effects of GCs during kainic acid-induced excitotoxicity by using previously characterized leukocyte-specific, GR-knockout mice. We will test the hypothesis that GR signaling in leukocytes is necessary for their increased recruitment and activation. We will also determine whether GR signaling in these cells affects the likelihood of neuron survival. The following aims are proposed to determine which of the observed effects of chronic GCs on inflammation and neuron death can be explained by leukocyte cell-autonomous GR signaling:

说明(申请人提供)：糖皮质激素(GC)是应激时从肾上腺释放的荷尔蒙，以其强大的多效性抗炎作用而闻名。在受损的中枢神经系统，在过度炎症危及神经元生存的情况下，它们的抗炎特性可能是有益的。因此，有必要具体了解GC如何影响大脑中的免疫反应，特别是考虑到新出现的证据表明，在某些情况下，GC并不能减少炎症，甚至可以在CMS损伤期间增强免疫反应的某些方面。众所周知，急性GC暴露可以增强局部炎症反应，而长期GC暴露则具有免疫抑制作用。然而，最近发现，慢性GC暴露增加了巨噬细胞、粒细胞和小胶质细胞对兴奋性毒性损伤的CMS渗透，并伴随着促炎细胞因子IL-1(I、TNF-α和IL-6)水平的升高。慢性GC暴露也被发现增强了外周暴露于内毒素时这些细胞因子和促炎转录因子NFicB的CMS信号。鉴于其众所周知的抗炎特性，令人惊讶的是，GC不仅不会钝化，反而会增强这些炎症反应。根据这些发现，慢性暴露于GCs可能会增强受损的CMS的炎症反应。慢性GC暴露可通过刺激CNS中存在的任何细胞中的任何GC受体亚型来加剧CNS炎症。GC存在两种不同的核激素受体，即GC受体(GR)和盐皮质激素受体(MR)。GR拮抗剂阻断GC增强的中枢神经系统炎症，暗示GR参与了这一现象；然而，尚不清楚GCs作用于哪种细胞类型(S)，从而导致这些促炎效应。GCs最有可能的神经免疫靶点是常驻的小胶质细胞和渗出到损伤部位的外周白细胞。这两种类型的细胞都表达GR，并在协调急性损伤的免疫反应中发挥作用。这项建议旨在通过使用先前表征的白细胞特异性GR基因敲除小鼠来测量GCs在红藻氨酸诱导的兴奋性毒性过程中的免疫细胞特异性效应。我们将检验这一假设，即白细胞中的GR信号是其增加招募和激活所必需的。我们还将确定这些细胞中的GR信号是否会影响神经元存活的可能性。为了确定慢性GCs对炎症和神经元死亡的观察到的影响中的哪些可以通过白细胞自主GR信号来解释，提出了以下目标：