Transduction of Psychological Stress into Systematic Inflammation by Mitochondrial DNA Signaling

通过线粒体 DNA 信号传导将心理压力转变成系统性炎症

• 批准号: 10574523
• 负责人: Brett A Kaufman
• 金额: $ 67.48万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574523
• 关键词: Acute; Adrenergic Receptor; Adult; Affect; Animals; Bacteria; Biological; Blood; Blood Platelets; Catecholamines; Cell physiology; Cells; Chronic; Cultured Cells; DNA; Data; Deoxyribonucleases; Dependence; Disease; Dose; Epinephrine; Event; Exposure to; Female; Fibroblasts; Foundations; Functional disorder; Genetic; Genome; Glucocorticoid Receptor; Glucocorticoids; Health; Hormones; Hour; Human; Hydrocortisone; Image; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injections; Interleukin-6; Kinetics; Laboratories; Leukocytes; Link; Lymphocyte; Major Depressive Disorder; Maps; Mediating; Mediator; Membrane; Mental Health; Mental disorders; Methods; Mitochondria; Mitochondrial DNA; Molecular; Molecular Structure; Mus; Nature; Neurosecretory Systems; Norepinephrine; Nuclear; Organelles; Outcome; Participant; Pathway interactions; Physiological; Physiological Processes; Physiology; Plasma; Positioning Attribute; Process; Production; Psychological Stress; Psychosocial Stress; Receptor Signaling; Recovery; Research Personnel; Rest; Risk; Role; Rupture; Series; Serum; Sex Differences; Signal Pathway; Signal Transduction; Signaling Molecule; Sorting; Specificity; Stress; Structure; Suicide attempt; Supplementation; System; TLR9 gene; TNF gene; Testing; Time; Travel; Trier Social Stress Test; Visit; Woman; Work; acute stress; aged; cellular imaging; circulating biomarkers; cytokine; digital; disorder risk; experience; immune activation; immunogenic; immunogenicity; improved; inflammatory marker; inhibitor; live cell imaging; male; men; molecular marker; monocyte; negative affect; neutrophil; novel; oxidation; psychologic; psychosocial; response; secondary analysis; stressor; systemic inflammatory response; volunteer

PROJECT SUMMARY Systemic inflammation is believed to contribute to the damaging health effects of psychological stress. In the laboratory setting, a single acute bout of socioevaluative stress leads to a delayed elevation of pro- inflammatory cytokines in healthy adults. However, the biological mechanisms by which psychological stress is transduced into inflammation is not well understood. A cellular component known to contribute to stress signaling is the mitochondrion – a bacteria-derived organelle with its own genome, the mitochondrial DNA (mtDNA). Recent evidence has demonstrated that various stressors induce the release of mitochondria- derived signaling molecules, or mitokines. Mitokines travel systemically and modulate central physiological processes, including immune cell function and the production of pro-inflammatory cytokines. One key mitokine is circulating cell-free mtDNA (ccf-mtDNA), which arises from mitochondrial extrusion of mtDNA, is recognized by the toll-like receptor 9 (TLR-9), and leads to pro-inflammatory cytokine production in animal and human cells. Our preliminary data showed that ccf-mtDNA release, but not ccf-nuclear DNA, is acutely induced following a brief experimental psychological stress in humans. Thus, we suggest that ccf-mtDNA may be a missing link in the stress-inflammation cascade. In parallel, imaging and molecular studies on cellular systems suggests that ccf-mtDNA may be rapidly induced by primary neuroendocrine stress mediators, including glucocorticoids. This proposal will use an experimental socio-evaluative stress task, counterbalanced with a control no-stress visit for each participant, to map the kinetics of reactivity and recovery in ccf-mtDNA and other stress mediators in healthy women and men. Aim 1 will establish: i) the magnitude and kinetics of ccf- mtDNA release; ii) the specificity of this response compared to nuclear DNA; iii) examine potential sex differences in this process; and iv) statistically test ccf-mtDNA as a mediator of the subsequent increase in pro- inflammatory cytokines. In Aim 2, cellular and molecular studies will determine: i) whether primary glucocorticoid and catecholamine stress hormones are sufficient to trigger ccf-mtDNA release in primary human cultured cells and isolated leukocytes; ii) image in living cells mtDNA release in response to stress signaling; and iii) document physical changes in mtDNA structure that contribute to ccf-mtDNA release. Finally, Aim 3 will establish: i) the capacity of ccf-mtDNA from peak ccf-mtDNA serum to activate cytokine production in target cells; ii) the structural form and accessibility of ccf-mtDNA in human serum (from Aim 1); and iii) the dependency on TLR-9 for immune activation. Overall, these studies will contribute mechanistic evidence for a novel mitochondria-mediated mechanisms for transducing stress into inflammation in humans. Outcomes from this work will identify new potential targets to improve stress-related mental health and inflammatory disorders.

项目摘要 全身性炎症被认为有助于心理压力对健康的破坏性影响。在 在实验室环境中，一次急性的社会评价压力会导致亲- 健康成人的炎症细胞因子。然而，心理压力的生物学机制是 转化为炎症的机制还不清楚。一种细胞成分， 信号是线粒体-一种细菌衍生的细胞器，具有自己的基因组，即线粒体DNA （mtDNA）。最近的证据表明，各种应激源诱导线粒体的释放， 衍生的信号分子或丝裂因子。丝裂素系统性传播并调节中枢生理功能 过程，包括免疫细胞功能和促炎细胞因子的产生。一个关键的丝裂因子 是循环无细胞线粒体DNA（ccf-mtDNA），它来自线粒体的mtDNA挤出， 通过toll样受体9（TLR-9），并导致动物和人类中促炎细胞因子的产生 细胞我们的初步数据表明，ccf-线粒体DNA的释放，而不是ccf-核DNA，是急性诱导 在人类短暂的实验性心理压力之后。因此，我们认为ccf-mtDNA可能是 压力-炎症级联反应中缺失的一环与此同时，对细胞系统的成像和分子研究 提示ccf-mtDNA可能被主要的神经内分泌应激介质快速诱导，包括 糖皮质激素这项建议将使用一个实验性的社会评价压力任务，与一个 对每个参与者进行对照无应激访视，以绘制ccf-mtDNA中反应性和恢复的动力学， 健康女性和男性中的其他压力介质。目标1将建立：i）ccf的大小和动力学- 线粒体DNA释放; ii）与核DNA相比，这种反应的特异性; iii）检查潜在的性别 在这个过程中的差异;和iv）统计学测试ccf-mtDNA作为随后的前- 炎性细胞因子在目标2中，细胞和分子研究将确定： 糖皮质激素和儿茶酚胺应激激素足以触发原发性肝癌中ccf-mtDNA的释放。 人培养细胞和分离的白细胞; ii）活细胞中响应于应激而释放mtDNA的成像 iii）记录有助于ccf-mtDNA释放的mtDNA结构的物理变化。最后， 目的3将建立：i）来自峰值ccf-mtDNA血清的ccf-mtDNA激活细胞因子产生的能力， 靶细胞; ii）ccf-mtDNA在人血清中的结构形式和可及性（来自Aim 1）;和iii） 依赖TLR-9进行免疫激活。总的来说，这些研究将为以下方面提供机械证据： 将压力转化为人类炎症的新的神经递质介导机制。的成果 这项工作将确定新的潜在目标，以改善与压力有关的心理健康和炎症性疾病。