The role of glucocorticoid signaling in immune cells during excitotoxicity.

描述（由申请人提供）：糖皮质激素（GCs）是肾上腺在压力下释放的激素，以其有效和多效抗炎作用而闻名。在受损的中枢神经系统中，它们的抗炎特性在过度炎症危及神经元存活的情况下可能是有益的。因此，重要的是具体了解GCs如何影响大脑中的免疫反应，特别是考虑到在某些情况下，GCs不会减少炎症，甚至可以增强CMS损伤期间的免疫反应。众所周知，急性GC暴露可增强局部炎症反应，而长期GC暴露则具有免疫抑制作用。然而，最近发现慢性GC暴露会增加巨噬细胞、粒细胞和小胶质细胞的CMS浸润，导致兴奋性毒性损伤，并伴有促炎细胞因子IL-1（i、TNF-a和IL-6）水平升高。慢性GC暴露也被发现增加了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，GCs不仅没有减弱，反而增加了这些炎症反应。基于这些发现，慢性暴露于GCs可能会增强受伤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受体亚型而升高CNS炎症。GC有两种不同的核激素受体，即GC受体（GR）和矿皮质激素受体（MR）。GR拮抗剂阻断gc增强的CNS炎症，暗示GR参与了这一现象；然而，目前尚不清楚GCs作用于哪种细胞类型，从而导致这些促炎作用。GCs最可能的神经免疫靶点是常驻的小胶质细胞和外渗到损伤部位的外周白细胞。这两种细胞类型都表达GR，并有助于协调急性损伤的免疫反应。该方案旨在通过使用先前表征的白细胞特异性、gr敲除小鼠来测量GCs在kainic酸诱导的兴奋性毒性期间的免疫细胞特异性效应。我们将检验白细胞中的GR信号对于它们增加募集和激活是必要的假设。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。为了确定观察到的慢性GCs对炎症和神经元死亡的哪些影响可以用白细胞自主GR信号来解释，我们提出了以下目的：

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: