Stress, Heat-Shock Proteins, and Innate Immunity

描述（由申请人提供）：暴露于急性（<4小时）精神或身体压力源会刺激一系列行为和生理反应，这些反应有助于促进战斗/逃跑反应并提高生物体的生存机会。在细胞水平上，对应激的一个重要且高度保守的反应是热休克蛋白的刺激，特别是热休克蛋白72 （Hsp 72）。虽然细胞内Hsp72的诱导机制和功能已经被深入研究，但直到最近才发现细胞外Hsp72 （crisp72）在暴露于精神或身体应激源后可以快速高浓度释放到血液中。eHsp72的释放似乎是一种跨物种和应激源的高度保守的反应，这使我们提出crisp72的释放可能是以前未被认识到的急性应激反应的特征。急性应激源暴露后细胞外Hsp72释放的性别、种类和应激源的普遍性、细胞来源、信号和功能在很大程度上仍未被探索。我们提供的初步数据表明，在暴露于各种应激源后，雄性和雌性、啮齿动物和人类血液中的crisp72浓度增加，这些应激源包括条件情境恐惧、掠夺性应激、尾部应激、约束应激、穷尽性运动应激和手击应激（人类）。此外，我们有证据表明eHsp72通过a1-肾上腺素能受体介导的机制从棕色脂肪组织（BAT）迅速（<15分钟）释放，因为a1-肾上腺素能阻断（prazosin）阻止应激诱导的血液中eHsp72的增加；肾上腺素能激动剂（NE）从BAT释放crisp72。此外，我们报道crisp72在体外刺激先天免疫细胞的NO和炎症细胞因子，并且这种作用在LPS的存在下被增强。最后，细菌攻击部位的crisp72促进炎症恢复，而应激诱导的crisp72释放（prazosin）的阻断和炎症部位crisp72的免疫中和都阻止了应激的积极作用。因此，我们提出，暴露于急性应激后释放的crisp72可能是免疫系统的内源性“危险信号”。因此，在存在细菌攻击的情况下，eHsp72增强巨噬细胞/中性粒细胞释放一氧化氮（NO）和炎症细胞因子，从而促进体内细菌攻击的杀伤和恢复。因此，我们假设，暴露于急性应激源会刺激棕色脂肪组织通过α 1-肾上腺素能受体介导的机制将crisp72释放到血液中，并提高crisp72的功能，以促进细菌攻击（大肠杆菌）存在时的先天免疫。

DESCRIPTION (provided by applicant): Exposure to an acute (<4 hrs) mental or physical stressor stimulates a cascade of behavioral & physiological responses that function to facilitate fight/flight responses and improve an organism's chances of survival. At the cellular level, one important and highly conserved response to stress is stimulation of heat shock proteins, specifically heat-shock protein 72 (Hsp 72). Although the mechanisms of induction and functions of intracellular Hsp72 have been thoroughly studied, only recently has it been discovered that extracellular Hsp72 (crisp72) can be rapidly released into the blood in high concentrations after exposure to either mental or physical stressors. The release of eHsp72 appears to be a highly conserved response across species and stressors, leading us to propose that crisp72 release may be a previously unrecognized feature of the acute stress response. The gender, species & stressor generalizability, cellular source(s), signal(s) and function(s) of extracellular Hsp72 released after acute stressor exposure remain largely unexplored. We present preliminary data that concentrations of crisp72 increase in the blood of males & females, and rodents & humans after exposure to a variety of stressors, i.e., conditioned contextual fear, predatory stress, tailshock stress, restraint stress, exhaustive exercise stress, and handshock stress (humans). In addition, we have evidence that eHsp72 is rapidly (<15min) released via an a1-adrenergic receptor mediated mechanism from brown adipose tissue (BAT) because a1-adrenergic blockade (prazosin) prevents stress-induced increases of eHsp72 in the blood; and an adrenergic agonist (NE) releases crisp72 from BAT. Furthermore, we report that crisp72 in vitro stimulates NO and inflammatory cytokines from innate immune cells, and this effect is potentiatied in the presence of LPS. Finally, crisp72 at the site of bacterial challenge facilitates inflammation recovery, and both blockade of stress-induced crisp72 release (prazosin) and immunoneutralization of crisp72 at the site of inflammation, prevents the positive effects of stress. We propose, therefore, that crisp72 released after exposure to acute stress may function as an endogenous "danger signal" for the immune system. Hence, in presence of bacterial challenge, eHsp72 potentiates macrophage/neutrophil release of nitric oxide (NO) & inflammatory cytokines resulting in facilitated killing & recovery from in vivo bacterial challenge. We hypothesize, therefore, that exposure to an acute stressor stimulates the release of crisp72 into the blood via an alpha1-adrenergic receptor-mediated mechanism from brown adipose tissue and elevated crisp72 functions to facilitate innate immunity in the presence of bacterial challenge (Escherichia coli).