Stress, Glucocorticoids and Neuroinflammatory Priming

描述（由申请人提供）：本提案探讨了在战斗/飞行紧急情况下应激反应中糖皮质激素（GC）作用的新概念。这是因为应激诱导的GCs的功能是提醒生物体的CNS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，这些信号或警报可以在一系列刺激（包括无菌损伤）下释放。在这里，GCs“启动”或“敏化”CNS对随后刺激的先天免疫/炎症反应，例如暴露于感染因子或损伤时发生的反应。这个想法是，应激诱导的GCs可以作为内分泌“警告信号”向中枢神经系统先天免疫系统发出，以诱导对随后的促炎刺激的预备反应（小胶质致敏）。鉴于中枢神经系统促炎细胞因子在精神疾病病因学中的新作用，神经炎症过程是这里的重点，其中压力和GCs是关键病因。主要目的是：1)探索应激如何使小胶质细胞对促炎刺激致敏；2)检查GCs是否介导应激诱导的小胶质细胞致敏。需要验证的一般假设是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介导内源性危险信号的促炎细胞因子作用。我们认为应激在应激后的一段时间内通过上调小胶质细胞上的tlr2和/或4来“启动”小胶质细胞。随后，小胶质细胞表达的上调TLRs感知暴露于促炎刺激后释放的内源性危险信号。B) TLR介导需要后期的促炎刺激增加大脑中作用于TLR的内源性分子。High Mobility Group Box1 （HMGB1）是一种在危险反应中释放的警报蛋白，是中枢神经系统中作用于TLRs的内源性蛋白，我们认为HMGB1在促炎刺激下增加，然后作用于应激上调的TLRs，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，大量证据表明GCs与此类疾病的病因有关。提出的工作可能为应激/GCs如何调节精神疾病的神经炎症过程提供有价值的见解。因此，目前的研究可能会导致应激/GCs作为精神疾病（即重度抑郁症，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). PUBLIC HEALTH RELEVANCE: Stress is a key factor in the development of mental health disorders and has been found to increase brain inflammation. Likewise, inflammation in the brain is also considered a key factor in the development of mental health disorders such as major depression. The present research studies how stress predisposes people to mental health disorder by focusing on how stress increases brain inflammation.