Stress, Heat-Shock Proteins, and Innate Immunity

压力、热休克蛋白和先天免疫

基本信息

批准号：
7426375
负责人：
MONIKA FLESHNER
金额：
$ 30.94万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426375
关键词：
Acute Adipose tissue Adrenergic Agents Adrenergic Agonists Adrenergic Receptor African Behavioral Blood Blood Circulation Brown Fat CD14 gene Cells Chemosensitization Complex Condition Cytolysis Data Disease Escherichia Escherichia coli Estrous Cycle Exercise Exposure to Female Fright Future Gender Goals HSP72 protein Heat shock proteins Host Defense Human Immune Immune system Immunology In Vitro Induced Hyperthermia Inflammation Inflammatory Investigation Kinetics Laboratory Finding Literature Measures Mediating Natural Immunity Necrosis Nitric Oxide Numbers Organism Papio Peptides Physiological Physiology Play Prazosin Proteins Psyche structure Receptor Activation Recovery Reporting Research Research Personnel Research Proposals Rodent Role Signal Transduction Site Source Staging Stress TLR2 gene TLR4 gene Testing Tissues Toll-like receptors Work acute stress adrenergic biological adaptation to stress cytokine extracellular fighting immune function improved in vivo in vivo Model innovation killings macrophage male neutrophil novel prevent programs psychologic response restraint stress stressor

项目摘要

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）的心理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/飞行反应并改善生物体的生存机会。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，特别是热冲蛋白72（HSP 72）。尽管对细胞内HSP72的诱导机制和功能进行了彻底的研究，但直到最近才发现细胞外HSP72（CRISP72）可以在暴露于精神或身体压力子后高浓度的血液中迅速释放到血液中。 EHSP72的释放似乎是在物种和压力源之间的高度保守反应，这使我们提出CRISP72释放可能是急性应激反应的先前未知的特征。急性应激暴露后释放的细胞外HSP72的性别，物种和应激源，细胞来源，信号和功能在很大程度上尚未探索。我们提供了初步数据，即CRISP72的浓度增加了男性和女性的血液，以及暴露于各种压力源后的啮齿动物和人类的血液，即条件性的情境恐惧，掠夺性压力，尾声压力，限制性压力，详尽的运动压力和手持压力（人类）。此外，我们有证据表明，通过棕色脂肪组织（BAT）的A1-肾上腺素能受体介导的机制释放EHSP72，因为A1-肾上腺素能阻断（prazosin）可以防止血液中EHSP72的胁迫诱导的增加；肾上腺素能激动剂（NE）从BAT中释放出Crisp72。此外，我们报告说，CRISP72体外刺激了先天免疫细胞的NO和炎性细胞因子，并且在LPS存在下这种作用会增强。最后，在细菌挑战部位的CRISP72促进了炎症的恢复，以及应压力诱导的CRISP72释放（prazosin）和在炎症部位的CRISP72免疫化的封锁，都可以防止压力的积极影响。因此，我们建议，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，在存在细菌挑战的情况下，EHSP72增强了一氧化氮（NO）和炎性细胞因子的巨噬细胞/中性粒细胞释放，从而促进了体内细菌挑战的杀伤和恢复。因此，我们假设暴露于急性应激源会通过棕色脂肪组织中的α1-肾上腺素能受体介导的机制刺激CRISP72释放到血液中，而CRISP72升高的功能升高，以促进细菌挑战的存在（Escherichia Coli）。