Mitochondrial DNA, chronic stress, and inflammation

慢性应激是发展多种精神疾病的风险因素，目前的治疗方法不足以治疗这些疾病。来自我们实验室和其他实验室的证据表明，慢性应激也可以在人类和动物模型中引发炎症加剧和夸大的炎症反应。然而，潜在的机制还没有被很好地理解。线粒体在慢性应激状态下受损和功能障碍，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源于线粒体诱导的炎症。通过移除受损的线粒体，有丝分裂在预防炎症方面发挥着核心作用。当这一过程被破坏时，mtDNA被释放，细胞外游离mtDNA(cf-mtDNA)促进Toll样受体9(TLR9)信号激活免疫系统。我们最近的研究发现，暴露在慢性束缚应激(RS)下的小鼠表现出神经炎症和社会行为缺陷。我们的初步数据显示，用DNase I治疗去除cf-mtDNA可以减轻RS诱导的社会行为缺陷和前额叶皮质(PFC)促炎标志物的增加。此外，我们发现线粒体DNA诱导的社会行为缺陷是TLR9依赖的。RS诱导小胶质细胞和神经元TLR9表达显著增加。在各种与线粒体吞噬相关的分子中，线粒体抗病毒信号蛋白(MAVS，一种线粒体适配器蛋白)信号的激活导致了促炎信号的产生。我们的初步研究结果表明，在MAVS KO小鼠中，RS诱导的cf-mtDNA增加是减弱的。此外，我们还发现RS后CDS T细胞的吞丝分裂功能受损，但CDS T细胞的吞噬功能受损。我们推测，CD4·T细胞线粒体DNA水平的增加通过激活TLR9参与了RS诱导的神经炎症和社会行为缺陷。目的1将确定RS诱导的线粒体DNA释放是否会导致神经炎症和社会行为减少。目的2研究线粒体DNA介导的神经元TLR9激活是否促进RS后的社会行为缺陷。目的3研究RS诱导的线粒体DNA释放是否依赖于有丝分裂。如果成功，我们的项目将在了解应激诱导的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或抑制应激相关心理健康障碍中的TLR9激活的药理学方法。

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.