Stress, Heat-Shock Proteins, and Innate Immunity

压力、热休克蛋白和先天免疫

• 批准号: 6893657
• 负责人: MONIKA FLESHNER
• 金额: $ 35.78万
• 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/6893657
• 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）精神或身体应激刺激一连串的行为和生理反应，其功能是促进战斗/逃跑反应并提高生物体的生存机会。在细胞水平，一个重要的和高度保守的应激反应是热休克蛋白，特别是热休克蛋白72（Hsp 72）的刺激。虽然细胞内Hsp 72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Hsp 72（crisp 72）在暴露于精神或身体应激后可以迅速释放到血液中。eHsp 72的释放似乎是一个高度保守的反应，跨物种和应激源，使我们提出，crisp 72释放可能是一个以前未被认识到的急性应激反应的功能。急性应激后细胞外Hsp 72的性别、物种和应激的普遍性、细胞来源、信号和功能尚不清楚。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、掠夺性应激、尾震应激、约束应激、力竭性运动应激和手震应激（人类）。此外，我们有证据表明，eHsp 72通过α 1-肾上腺素能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α 1-肾上腺素能阻滞剂（哌唑嗪）阻止了血液中应激诱导的eHsp 72增加;肾上腺素能激动剂（NE）从BAT中释放crisp 72。此外，我们报告说，crisp 72在体外刺激NO和炎症细胞因子从先天免疫细胞，这种效果是potentiatied在LPS的存在下。最后，细菌攻击部位的crisp 72促进炎症恢复，并且阻断应激诱导的crisp 72释放（哌唑嗪）和crisp 72在炎症部位的免疫中和，防止应激的积极作用。因此，我们提出，暴露于急性应激后释放的crisp 72可能作为免疫系统的内源性“危险信号”。因此，在存在细菌攻击的情况下，eHsp 72增强巨噬细胞/嗜中性粒细胞释放一氧化氮（NO）和炎性细胞因子，导致促进体内细菌攻击的杀伤和恢复。因此，我们假设，暴露于急性应激刺激crisp 72释放到血液中，通过α 1-肾上腺素能受体介导的机制从棕色脂肪组织和升高crisp 72功能，以促进先天免疫的存在下，细菌的挑战（大肠杆菌）。