Stress, Heat-Shock Proteins, and Innate Immunity

压力、热休克蛋白和先天免疫

• 批准号: 7071681
• 负责人: MONIKA FLESHNER
• 金额: $ 34.94万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071681
• 关键词: Escherichia coli; adrenergic receptor; baboons; brown fat; conditioning; cytokine; estrus; extracellular; fear; gender difference; heat shock proteins; hormone regulation /control mechanism; immunity; inflammation; laboratory rat; macrophage; neutrophil; nitric oxide; protein biosynthesis; protein structure function; stress; stressor

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).

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，从而促进战斗/逃跑反应并提高生物体的生存机会。在细胞水平上，对应激的一种重要且高度保守的反应是刺激热休克蛋白，特别是热休克蛋白 72 (Hsp 72)。尽管细胞内Hsp72的诱导机制和功能已被深入研究，但直到最近才发现细胞外Hsp72（crisp72）在受到精神或身体压力后可以高浓度快速释放到血液中。 eHsp72 的释放似乎是跨物种和应激源的高度保守的反应，这使我们提出，crisp72 的释放可能是急性应激反应的一个先前未被认识的特征。急性应激源暴露后释放的细胞外 Hsp72 的性别、物种和应激源普遍性、细胞来源、信号和功能在很大程度上仍未得到探索。我们提供的初步数据表明，在暴露于各种压力源（即条件性情境恐惧、捕食压力、尾震压力、束缚压力、力竭运动压力和手震压力（人类））后，男性和女性、啮齿动物和人类血液中的crisp72浓度会增加。此外，我们有证据表明，eHsp72 通过 α1 肾上腺素受体介导的机制从棕色脂肪组织 (BAT) 中快速（<15 分钟）释放，因为α1 肾上腺素受体阻断剂（哌唑嗪）可防止血液中应激诱导的 eHsp72 增加；肾上腺素能激动剂 (NE) 从 BAT 中释放 crisp72。此外，我们报告，crisp72 在体外刺激先天免疫细胞中的 NO 和炎症细胞因子，并且这种作用在 LPS 存在的情况下得到增强。最后，细菌攻击部位的crisp72促进炎症恢复，并且阻断应激诱导的crisp72释放（哌唑嗪）和炎症部位的crisp72免疫中和，可以防止应激的积极影响。因此，我们认为，暴露于急性应激后释放的crisp72可能充当免疫系统的内源性“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灭和恢复。因此，我们假设，暴露于急性应激源会通过棕色脂肪组织的α1-肾上腺素受体介导机制刺激crisp72释放到血液中，并提高crisp72的功能，以在细菌攻击（大肠杆菌）的情况下促进先天免疫。