Mitochondrial DNA, chronic stress, and inflammation

线粒体 DNA、慢性压力和炎症

• 批准号: 10664066
• 负责人: Anilkumar Pillai
• 金额: $ 44.57万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664066
• 关键词: 2019-nCoV; Adaptor Signaling Protein; Affect; Animal Model; Attenuated; Behavioral; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic stress; Cytosine; DNA; Data; Deoxyribonuclease I; Development; Dissection; Emotional; Exhibits; Exposure to; Functional disorder; Genetic; Goals; Guanine; Immune system; Impairment; Inflammation; Inflammatory Response; Intervention; Knockout Mice; Laboratories; Mediating; Mental Health; Mental disorders; Microglia; Mission; Mitochondria; Mitochondrial DNA; Mus; National Institute of Mental Health; Neurons; Pharmacology; Play; Prefrontal Cortex; Process; Public Health; Risk Factors; Role; SARS-CoV-2 infection; Signal Transduction; Signaling Protein; Social Behavior; Stress; Stressful Event; T-Lymphocyte; TLR9 gene; Testing; Therapeutic; Treatment Efficacy; United States National Institutes of Health; Work; antagonist; chemokine; cytokine; experimental study; extracellular; fetal; human model; improved; inorganic phosphate; insight; mental health related disorder; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; novel therapeutic intervention; prevent; response; restraint stress; social; social deficits

Chronic stress is a risk factor for the development of multiple psychiatric disorders for which current treatments are inadequate. Evidence from our laboratory and others suggest that chronic stress can also provoke elevated inflammation and exaggerated inflammatory responses in both humans and animal models. However, the underlying mechanisms are not well understood. Mitochondria become damaged and dysfunctional following chronic stress conditions raising the question of whether neuroinflammation associated with chronic stress-related neuropsychiatric conditions is due to mitochondria-induced inflammation. By removing damaged mitochondria, mitophagy plays a central role in preventing inflammation. When this process is impaired, mtDNA is released and the extracellular cell free mtDNA (cf-mtDNA) promotes Toll-like receptor 9 (TLR9) signaling to activate immune system. Our recent study found that mice exposed to chronic restraint stress (RS) exhibit neuroinflammation and social behavior deficits. Our preliminary data show that depletion of cf-mtDNA with DNase I treatment attenuates RS-induced deficits in social behavior and increases in proinflammatory markers in the prefrontal cortex (PFC). Furthermore, we found that mtDNA-induced deficits in social behavior are TLR9-dependent. Also, RS induced significant increases in TLR9 expression in microglia and neurons. Among the various mitophagy-related molecules, activation of Mitochondrial antiviral-signaling protein (MAVS, a mitochondrial adaptor protein)signaling results in proinflammatory signaling. Our preliminary findings showed that RS-induced increase in cf-mtDNA is attenuated in MAVS KO mice. Also, we found impaired mitophagy in CD4+, but not CDS+ T cells following RS. We hypothesize that increased levels of mtDNA from CD4• T cells contribute to RS-induced neuroinflammation and social behavior deficits via TLR9 activation. Aim 1 will determine whether RS-induced mtDNA release drives neuroinflammation and reduced social behavior. Aim 2 will examine whether mtDNA-mediated activation of TLR9 on neurons promotes social behavior deficits following RS. Aim 3 will examine whether mtDNA release induced by RS is dependent on mitophagy. If successful, our project will create new developments in understanding the mechanism mediating stress-induced neuroinflammation social behavior deficits, and thereby allow the development of pharmacological approaches to inhibit mtDNA release, neutralize extracellular cf-mtDNA, or inhibit TLR9 activation in stress-related mental health disorders.

慢性压力是多种精神疾病发展的一个危险因素，而目前的治疗方法还不充分。来自我们实验室和其他实验室的证据表明，在人类和动物模型中，慢性应激也会引起炎症升高和炎症反应的夸大。然而，其潜在机制尚不清楚。线粒体在慢性应激条件下变得受损和功能失调，这提出了一个问题，即与慢性应激相关的神经精神疾病相关的神经炎症是否由于线粒体诱导的炎症。通过移除受损的线粒体，线粒体自噬在预防炎症中起着核心作用。当这一过程受损时，mtDNA被释放，细胞外细胞游离mtDNA （cf-mtDNA）促进toll样受体9 （TLR9）信号传导，激活免疫系统。我们最近的研究发现，暴露于慢性约束应激（RS）的小鼠表现出神经炎症和社会行为缺陷。我们的初步数据表明，用DNase I治疗cf-mtDNA的消耗可以减轻rs引起的社会行为缺陷，并增加前额皮质（PFC）中的促炎标志物。此外，我们发现mtdna诱导的社会行为缺陷依赖于tlr9。此外，RS诱导TLR9在小胶质细胞和神经元中的表达显著增加。在各种与线粒体自噬相关的分子中，线粒体抗病毒信号蛋白（MAVS，一种线粒体接头蛋白）信号的激活导致促炎信号的产生。我们的初步研究结果表明，rs诱导的cf-mtDNA增加在MAVS KO小鼠中减弱。此外，我们发现RS后CD4+细胞的线粒体自噬受损，而CDS+ T细胞则没有。我们假设CD4•T细胞mtDNA水平的增加通过TLR9激活导致RS诱导的神经炎症和社会行为缺陷。目的1将确定rs诱导的mtDNA释放是否会导致神经炎症和减少社会行为。Aim 2将研究mtDNA介导的TLR9在神经元上的激活是否会促进RS后的社会行为缺陷。Aim 3将研究RS诱导的mtDNA释放是否依赖于线粒体自噬。如果成功，我们的项目将在理解介导应激性神经炎症社会行为缺陷的机制方面取得新的进展，从而允许开发抑制mtDNA释放、中和细胞外cf-mtDNA或抑制应激相关精神健康障碍中TLR9激活的药理学方法。