Stress, Glucocorticoids and Neuroinflammatory Priming

描述（由申请人提供）：本提案探讨了糖皮质激素（GC）在战斗/飞行紧急情况下应激反应中作用的新概念。这是应激诱导的GC用于警告生物体的CNS先天免疫系统潜在的“危险”信号，包括1）外源性病原体和/或病原体相关分子模式（PAMP），和2）内源性危险信号或警报素，其可以响应于包括无菌损伤在内的广泛刺激而释放。在此，GC“引发”或“敏化”CNS先天免疫/炎性应答以随后刺激，例如在暴露于感染剂或损伤时发生。这个想法是，应激诱导的GC可以作为一个内分泌的“警告信号”，中枢神经系统先天免疫系统诱导一个预备性反应（小胶质细胞致敏），随后的促炎刺激。神经炎症过程是一个焦点，因为中枢神经系统促炎细胞因子在精神疾病的病因学中发挥着重要作用，其中应激和GC是关键的病因学因素。主要目标是：1）探索应激如何使小胶质细胞对促炎性挑战敏感; 2）检查GC是否介导应激诱导的小胶质细胞敏感化。 待测试的一般假设是A）应激通过上调小胶质细胞上的模式识别受体（PRR）使小胶质细胞对促炎刺激敏感。PRRs Toll样受体（TLR）2和/或4抑制内源性危险信号的促炎细胞因子作用。我们建议，压力“启动”小胶质细胞通过上调TLR 2和/或4的小胶质细胞一段时间后的压力。随后，由小胶质细胞表达的上调的TLR感知在暴露于促炎刺激物时释放的内源性危险信号。B）TLR介导需要后期促炎刺激增加脑中作用于TLR的内源性分子。高迁移率族蛋白盒1（HMGB 1）是一种在危险时释放的警报素，是中枢神经系统中作用于TLR的内源性蛋白质，我们认为HMGB 1通过促炎刺激增加，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）GC介导小胶质细胞的应激诱导的敏化（即TLR 2/4的上调）。 临床上，应激和神经炎症过程正在成为精神疾病病因学中的重要因素。此外，大量的证据表明GC与此类疾病的病因有关。拟议的工作可能会提供有价值的洞察压力/GC如何调节神经炎症过程中的精神疾病。因此，目前的研究可能会导致压力/GC作为精神疾病（即重性抑郁症，PTSD）病因学中的神经炎症易感因素的重新概念化。

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).