Mitochondrial DNA, chronic stress, and inflammation

慢性压力是导致多种精神疾病的一个危险因素，而目前的治疗方法对此并不充分。来自我们实验室和其他实验室的证据表明，慢性压力也可以在人类和动物模型中引起炎症升高和炎症反应加剧。然而，其基本机制尚未得到很好的理解。线粒体在慢性应激条件下变得受损和功能障碍，这提出了与慢性应激相关的神经精神疾病相关的神经炎症是否是由于线粒体诱导的炎症的问题。通过去除受损的线粒体，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，细胞外游离mtDNA（cf-mtDNA）促进Toll样受体9（TLR 9）信号传导以激活免疫系统。我们最近的研究发现，暴露于慢性束缚应激（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，DNase I治疗的cf-mtDNA的耗竭减弱了RS诱导的社会行为缺陷，并增加了前额叶皮层（PFC）中的促炎标记物。此外，我们发现mtDNA诱导的社会行为缺陷是TLR 9依赖的。此外，RS诱导TLR 9在小胶质细胞和神经元中的表达显著增加。在各种线粒体吞噬相关分子中，线粒体抗病毒信号蛋白（MAVS，线粒体适配蛋白）信号的激活导致促炎信号。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，我们发现受损的线粒体自噬的CD 4+，但不CDS+ T细胞后RS。我们推测，来自CD 4· T细胞的mtDNA水平的增加通过TLR 9活化而导致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释放是否驱动神经炎症和减少的社会行为。目的2将研究是否mtDNA介导的激活TLR 9的神经元促进社会行为缺陷后RS。目的3研究RS诱导的线粒体DNA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，从而允许开发药物方法来抑制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TLR 9激活。

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.