Pro-inflammatory glucocorticoid effects in the CNS

描述（由申请人提供）：糖皮质激素（GCs）是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存活的能力。这些有害影响通常被认为与受损大脑中GCs的抗炎作用的益处相抵消。然而，实际上，GCs在受伤大脑中的抗炎作用并不像人们通常认为的那样持久。此外，作为对教条的一个明显挑战，我的实验室和其他人最近的工作表明，GCs甚至可以增强受伤的海马体和皮层的炎症（而在大脑的其他地方通常是消炎的）。具体来说，这种激素增加了炎症细胞向损伤部位的迁移、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具有挑战性（即，揭示GCs如何在不同背景下对炎症产生相反的影响）；此外，它们具有相当大的潜在临床意义，因为人工合成的GCs被广泛用于控制人脑损伤后的炎症。该提案将在比以前的研究更简化的水平上研究这些新型GC作用的机制。在所有的实验中，完整的大鼠要么暴露于LPS（一种细菌衍生的分子，能刺激强烈的炎症反应），要么暴露于诱发癫痫发作的兴奋毒素（也会引起大脑炎症）。具体目标1将分析GC暴露的强度和持续时间，其与这些炎症挑战之一的时间关系，以及检查的大脑区域如何决定GC是加重还是减弱这些挑战引起的炎症。从这些数据中，我们将确定GCs增强与炎症钝化之间最显著的差异。在特异性目标2中，我们将确定区分这两种状态的基因表达谱；具体来说，我们将根据激素是增强还是抑制，确定其表达以不同方式受到gc影响的基因。然后，特异性Aim 3将确定发生这些表达差异的细胞类型（即，无论是在神经元、星形胶质细胞、小胶质细胞、内皮细胞、中性粒细胞还是巨噬细胞中）。公共卫生相关性：糖皮质激素（GCs，包括合成皮质类固醇，如氢化可的松或泼尼松）具有抗炎作用，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，在一些急性神经损伤后，GCs实际上会加重炎症。该提案开始剖析这些意想不到的和破坏性的促炎GC效应的分子机制。

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.