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)：暴露在急性(&lt；4小时)精神或身体应激源中会刺激一连串的行为和生理反应，这些反应的功能是促进战斗/逃跑反应，并提高有机体的生存机会。在细胞水平上，对应激的一个重要且高度保守的反应是对热休克蛋白的刺激，特别是热休克蛋白72(HSP72)。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)在精神或身体应激源作用下可以迅速释放到血液中。EHsp72的释放似乎是一种跨物种和应激源的高度保守的反应，这导致我们提出CRISP72的释放可能是以前未被认识到的急性应激反应的特征。急性应激源暴露后释放的胞外HSP72的性别、种类和应激源概化、细胞来源(S)、信号(S)和功能(S)仍未得到很大程度的探讨。我们提供的初步数据表明，在暴露于各种应激源后，雄性和雌性以及啮齿动物和人类的血液中CRISP72的浓度都会增加，这些应激源包括条件性背景恐惧、捕食应激、尾部应激、束缚应激、精疲力竭运动应激和手震应激(人类)。此外，我们有证据表明，eHSP72可以通过A1-肾上腺素能受体介导的机制从棕色脂肪组织(BAT)迅速释放出来，因为A1-肾上腺素能受体阻滞剂(哌唑嗪)可以阻止应激诱导的血液中eHSP72的增加；而肾上腺素能激动剂(NE)则从BAT释放CRISP72。此外，我们报道了CRISP72在体外刺激天然免疫细胞产生的NO和炎性细胞因子，并且这种作用在脂多糖的存在下被增强。最后，细菌攻击部位的CRISP72促进炎症恢复，阻断应激诱导的CRISP72释放(哌唑嗪)和炎症部位CRISP72的免疫中和作用，都可以阻止应激的积极作用。因此，我们认为，暴露于急性应激后释放的CRISP72可能作为免疫系统的内源性“危险信号”发挥作用。因此，在细菌攻击存在的情况下，eHSP72促进巨噬细胞/中性粒细胞释放一氧化氮(NO)和炎性细胞因子，从而促进体内细菌攻击的杀伤和恢复。因此，我们假设，暴露在急性应激源下，通过α1肾上腺素能受体介导的机制，刺激棕色脂肪组织中CRISP72释放到血液中，并提高CRISP72的功能，以促进在细菌挑战(大肠杆菌)存在的情况下的先天性免疫。