Pro-inflammatory glucocorticoid effects in the CNS

描述(申请人提供)：糖皮质激素(GC)，应激时分泌的肾上腺类固醇，可损害神经元在坏死性神经损伤中生存的能力。这些有害的影响通常被认为被GCs在受损大脑中的抗炎作用所抵消。然而，GC实际上在受损的大脑中的抗炎作用并不像人们通常认为的那样持续。此外，作为对教条的一个明显挑战，我的实验室和其他实验室最近的研究表明，GC甚至可以增强受损的海马体和皮质的炎症方面(同时在大脑其他地方具有经典的抗炎作用)。具体地说，该激素促进炎症细胞向损伤部位的迁移，促进促炎细胞因子的表达和蛋白水平，以及促炎转录因子NFkB的激活。这些发现在基础科学层面上具有挑战性(即，揭示GC如何在不同的环境中对炎症产生相反的影响)；此外，考虑到合成GC在控制人脑侮辱后炎症方面的巨大使用，它们具有相当大的潜在临床意义。这项建议将在比以前的研究更简单化的水平上研究这些新的GC作用背后的机制。在所有实验中，完好无损的大鼠将暴露于细菌衍生的分子，刺激强烈的炎症反应的内毒素，或癫痫诱导的兴奋性毒素，后者也会导致大脑发炎。具体目标1将分析GC暴露的大小和持续时间，它与这些炎症挑战之一的时间关系，以及被检查的大脑区域如何确定GC是加剧还是钝化这些挑战造成的炎症。从这些数据中，我们将确定GC增强和炎症钝化的条件之间最显著的对比。在特定的目标2中，我们将识别区分这两种状态的基因表达谱；具体地说，我们将根据激素是增强还是抑制，识别其表达受到GC以相反方式影响的基因。然后，特殊目标3将确定出现这些表达差异的细胞类型(即，是否在神经元、星形胶质细胞、小胶质细胞、内皮细胞、中性粒细胞或巨噬细胞中)。与公共健康相关：糖皮质激素(GC，包括合成的皮质类固醇，如氢化可的松或泼尼松)是抗炎的，被广泛用于减少脑损伤后发生的破坏性炎症。然而，越来越多的文献表明，GC实际上可以在一些急性神经侮辱后加重炎症。该提案开始剖析这些意想不到和破坏性的促炎GC效应背后的分子机制。

DESCRIPTION (provided by applicant): Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of neurons to survive necrotic neurological insults. These deleterious effects have often been viewed as counterbalanced by the benefits of the anti-inflammatory actions of GCs in the injured brain. However, GCs are actually less consistently anti-inflammatory in the injured brain than generally assumed. Moreover, as a marked challenge to dogma, recent work from my lab and others has shown that GCs can even potentiate aspects of inflammation in the injured hippocampus and cortex (while being classically anti-inflammatory elsewhere in the brain). Specifically, the hormone augments the migration of inflammatory cells to the injury site, the expression of and protein levels of pro-inflammatory cytokines, and the activation of the pro- inflammatory transcription factor NFkB. These findings are challenging at the basic science level (i.e., uncovering how GCs can have opposite effects on inflammation in different contexts); moreover, they are of considerable potential clinical relevance, given the enormous use of synthetic GCs to control post-insult inflammation in the human brain. This proposal will study the mechanisms underlying these novel GC actions at a more reductive level than in previous studies. In all experiments, intact rats will be exposed to either LPS, a bacteria-derived molecule which stimulates a robust inflammatory response, or a seizure-inducing excitotoxin, which also causes inflammation in the brain. Specific Aim 1 will analyze how the magnitude and duration of GC exposure, its temporal relationship to one of these inflammatory challenges, and the brain region examined determine whether GCs worsen or blunt the inflammation caused by these challenges. From these data, we will identify the most striking contrasts between conditions where GCs augment versus blunt facets of inflammation. In Specific Aim 2, we will identify gene expression profiles that differentiate between those two states; specifically, we will identify genes whose expression is influenced in a contrasting manner by GCs, depending on whether the hormone is enhancing or inhibiting. Specific Aim 3 will then identify the cell types in which these expression differences are occurring (i.e., whether in neurons, astrocytes, microglia, endothelial cells, neutrophils or macrophages). PUBLIC HEALTH RELEVANCE: Glucocorticoids (GCs, including synthetic corticosteroids such as hydrocortisone or prednisone) are anti-inflammatory, and are widely used to decrease the damaging inflammation that occurs after brain injury. However, a growing literature shows that GCs can actually worsen inflammation following some acute neurological insults. The proposal begins to dissect the molecular mechanisms underlying these unexpected and damaging pro-inflammatory GC effects.