Stress, Glucocorticoids and Neuroinflammatory Priming

描述(由申请人提供)：本提案探索了糖皮质激素(GC)在战斗/逃跑紧急情况下应激反应中作用的新概念。这就是说，应激诱导的GC功能是提醒有机体的中枢神经系统先天免疫系统注意潜在的“危险”信号，这些信号包括：1)外源性病原体和/或病原体相关分子模式(PAMPs)；2)内源性危险信号或警报，这些信号可以在包括无菌损伤在内的一系列刺激下释放。在这里，GC“启动”或“敏化”CNS对后续刺激的先天免疫/炎症反应，例如接触感染性物质或损伤时发生的刺激。其想法是，应激诱导的GC可以作为中枢神经系统先天免疫系统的内分泌“警告信号”，以诱导对随后的促炎刺激的预备反应(小胶质细胞敏化)。鉴于中枢神经系统促炎细胞因子在精神障碍的病因学中的新角色，神经炎性过程是这里的一个焦点，在精神障碍中，应激和GC是关键的病因因素。主要目的是：1)探索应激如何使小胶质细胞对促炎挑战敏感；2)检测GCs是否介导了应激诱导的小胶质细胞敏化。需要检验的一般假设是：A)应激通过上调小胶质细胞上的模式识别受体(PRRs)，使小胶质细胞对促炎刺激敏感。PRRs Toll样受体(TLR)2和/或4转导内源性危险信号的促炎细胞因子效应。我们认为，应激通过在应激后一段时间内上调小胶质细胞上的TLR2和/或TLR4来启动小胶质细胞。随后，小胶质细胞表达的上调的TLRs感觉到暴露于促炎刺激时释放的内源性危险信号。B)TLR调节需要较晚的促炎刺激增加大脑中作用于TLR的内源性分子。高迁移率族蛋白1(HMGB1)是一种在危险时释放的警报蛋白，是中枢神经系统中的一种内源性蛋白，作用于TLR&我们认为HMGB1在促炎刺激下增加，然后作用于应激上调的TLR，从而诱导增强的促炎细胞因子反应。C)GCs介导应激诱导的小胶质细胞敏化(即TLR2/4上调)。在临床上，应激和神经炎症过程正在成为精神疾病的病因学中的重要因素。此外，大量证据表明GC与此类疾病的病因学有关。这项拟议的工作可能会为应激/GC如何调节精神障碍中的神经炎症过程提供有价值的见解。因此，本研究可能导致在精神障碍(即重度抑郁，PTSD)的病因学中将应激/GC重新定义为神经炎性诱因。

DESCRIPTION (provided by applicant): The present proposal explores a novel conceptualization of glucocorticoid (GC) action in the stress response during a fight/flight emergency. This is that stress-induced GCs function to alert the organism's CNS innate immune system to potential "danger" signals that include 1) exogenous pathogens and/or pathogen associated molecular patterns (PAMPs), & 2) endogenous danger signals or alarmins, which can be released in response to a wide array of stimuli including sterile injury. Here, GCs "prime" or "sensitize" the CNS innate immune/inflammatory response to subsequent stimulation, such as occurs upon exposure to infectious agents or injury. The idea is that stress-induced GCs can function as an endocrine "warning signal" to the CNS innate immune system to induce a preparatory response (microglial sensitization) to subsequent proinflammatory stimuli. Neuroinflammatory processes are a focus here given the emerging roles of CNS pro-inflammatory cytokines in the etiology of psychiatric disorders in which stress & GCs are key etiologic factors. The primary objectives are: 1) to explore how stress sensitizes microglia to pro-inflammatory challenges & 2) examine whether GCs mediate stress-induced sensitization of microglia. The general hypotheses to be tested are that A) stress sensitizes microglia to pro-inflammatory stimuli by upregulating pattern recognition receptors (PRRs) on microglia. The PRRs Toll-Like receptor (TLR) 2 and/or 4 transduce the pro-inflammatory cytokine effects of endogenous danger signals. We propose that stress "primes" microglia by upregulating TLR 2 and/or 4 on microglia for a period of days post-stress. Subsequently, upregulated TLRs expressed by microglia sense endogenous danger signals released upon exposure to a pro- inflammatory stimulus. B) TLR mediation requires that the later pro-inflammatory stimulus increase an endogenous molecule in the brain that acts at the TLRs. High Mobility Group Box1 (HMGB1), an alarmin released in response to danger, is an endogenous protein in the CNS that acts at TLRs & we suggest that HMGB1 is increased by a pro-inflammatory stimulus & then acts at the stress-upregulated TLRs, thereby inducing a potentiated pro-inflammatory cytokine response. C) GCs mediate the stress-induced sensitization of microglia (i.e. upregulation of TLR 2/4). Clinically, stress and neuroinflammatory processes are emerging as important factors in the etiology of psychiatric disorders. Also, an extensive body of evidence implicates GCs in the etiology of such disorders. The proposed work may provide valuable insight into how stress/GCs regulate neuroinflammatory processes in psychiatric disorders. Thus, the present research may lead to a reconceptualization of stress/GCs as neuroinflammatory predisposing factors in the etiology of psychiatric disorders (i.e. major depression, PTSD).