Cell |阐明CD4+ T细胞的嘌呤合成紊乱与压力引发的焦虑症间的重要联系

2019-11-01 BioArt BioArt

恐惧和压抑等情绪反应是我们生活中对消极情况的正常心理和生理反应。频繁的急性情绪反应是一种病理状态,被称为慢性应激。科学技术和物质文明高度发达的今天,人们内在平和与快乐的情绪却没有跟随着增长,几乎每个人都或多或少感到压力,长期的慢性应激压力会增加抑郁和焦虑的患病风险。严重的焦虑会把人拖入烦恼的恶性循环,从精神和肉体方面产生不断的内耗,最终造成难以挽回的损伤。

恐惧和压抑等情绪反应是我们生活中对消极情况的正常心理和生理反应。频繁的急性情绪反应是一种病理状态,被称为慢性应激。科学技术和物质文明高度发达的今天,人们内在平和与快乐的情绪却没有跟随着增长,几乎每个人都或多或少感到压力,长期的慢性应激压力会增加抑郁和焦虑的患病风险。严重的焦虑会把人拖入烦恼的恶性循环,从精神和肉体方面产生不断的内耗,最终造成难以挽回的损伤。

随着现代生活节奏的加快,多压力状态下诱发的精神类疾病呈现爆发式的增长。根据我国部分地区的调查结果进行估算:在15岁以上人口中,我国各类精神疾病患者人数已超过1亿人,其中多为抑郁症、焦虑症和自闭症等精神障碍或心理行为异常的患者。长期以来,抑郁症、自闭症等致病原因都被认为来源于中枢神经系统本身,而忽视了机体的其他组织器官在此过程中的功能,关于异常心理学和线粒体形态学的相关知识主要集中在神经元上。

近些年,随着肠-脑轴研究的深入,多项研究表明肠道菌群参与焦虑和抑郁症的发生。有证据显示,肠道炎症性疾病,如肠应激综合征,溃疡性结肠炎患者,往往会伴有焦虑抑郁情绪,预示着免疫细胞可能也参与精神类疾病的发生。中枢神经系统传统上被认为是免疫豁免的组织之一。除了小胶质细胞, 稳态下的中枢神经系统被认为是不存在其他的免疫细胞如T细胞、B细胞等。因此,研究人员和医生常用外周免疫细胞的浸润程度来指示中枢神经系统的病理进程。许多开创性的研究探索了先天免疫与中枢神经系统在压力、暴食或厌食、发烧等条件下的相互作用。但适应性免疫系统在此过程中的功能,我们尚知之甚少。

免疫系统与心理疾病的相互作用已成为免疫学研究的热点之一。最近的一项研究表明,嗜睡症可能是一种自身免疫性疾病,在这种疾病中,自体细胞毒性CD8+ T细胞促使神经元产生下视丘分泌素以调节觉醒状态。活化的T细胞源细胞因子,包括IFN-γ,IL-4和IL-33被证明参与调节神经元发育和活动。还没有证据表明静息状态下的T细胞是否也参与了神经系统的稳态调节。除了行为改变,慢性应激还会导致免疫代谢和心血管系统的紊乱。早期研究显示慢性应激与系统免疫反应的功能障碍有关,研究主要集中在抑郁症或焦虑症患者的体内免疫平衡和免疫系统的维持。慢性应激诱导的免疫系统变化包括白细胞运输减少、中性粒细胞吞噬功能受损和外周淋巴细胞数量减少。目前的研究已经发现了多种免疫分子在心理疾病中的生理功能。来源于先天免疫细胞的IL-6和IL-1B在许多方面影响中枢神经系统,包括小鼠的神经递质代谢、神经内分泌功能和神经塑性。最新研究表明,适应性免疫也参与了中枢神经系统的维持。来源于脑膜T细胞的IFN-γ作用于前额叶皮质神经元,抑制GABAergic并防止异常兴奋。其他新的证据显示在T细胞中敲除pdcd1可导致色氨酸和酪氨酸减少,导致神经递质缺乏和焦虑样行为。

免疫学家们很早就发现了焦虑症,抑郁症病人的外周免疫应答存在着异常。与正常对照组相比, 这类患者大多数表现为免疫功能低下。2017年日本Sidonia Fagarasan团队发现,PD-1抗体引发的T细胞持续活化会导致小鼠焦虑行为的发生,而他们认为这些T细胞是通过过度消耗外周的色氨酸和酪氨酸来实现的。但这些发现与临床焦虑症患者外周T细胞明显降低相悖,因此外周T细胞在慢性应激诱导产生的焦虑行为中的具体功能,及其与中枢神经细胞之间的互作方式尚不明确。

2019年10月31日,浙江大学生命科学研究院靳津实验室联合东南大学柴人杰实验室在Cell杂志发表了题为“Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior”的研究论文,揭示了CD4+T细胞嘌呤合成代谢功能紊乱在慢性应激诱导的心理疾病中的重要功能。

作者团队首先发现,T、B细胞的Rag1-/-小鼠明显对反复电击诱导的焦虑情绪具有明显的抵抗,抗体中和试验进而证明,在此过程中CD4+T细胞对于慢性压力引发的焦虑行为具有核心的调控作用。在另一种慢性束缚模型中,作者们也观察到了类似的现象。国际转移实验表明,来源于焦虑小鼠的CD4+T细胞具有了“焦虑”印记,在没有压力处理的Rag1-/-小鼠中,直接引发了焦虑行为的发生。有趣地是,作者通过比较静息状态的T细胞和效应性T细胞,发现引发焦虑行为的这群CD4+T细胞并不依赖其自身的活化状态,这与T细胞的活化才是其发挥功能的关键的传统观点相悖,说明T细胞仍有我们尚不明确的发挥作用的方式。

作者们通过转录组测序发现,压力应激的CD4+T细胞上调多种线粒体基因。免疫荧光的结果进而证明,这些T细胞的线粒体更多地呈现分裂的表型。作者证明,压力会促进白三烯B4等促炎物质的生成,白三烯B4可能是导致外周T细胞线粒体分裂的直接“元凶”,没有外周CD4+T细胞,这些物质也不在具有诱导焦虑行为的能力。众所周知,线粒体的融合过程是由多个蛋白的协同介导的,如MIGA2,MFN1,MFN2等。作者通过这些基因的T细胞特异性敲除小鼠(MIGA2TKO,MFN1/2TKO),证明T细胞中线粒体的分裂形态直接导致了焦虑行为的产生,这些小鼠同时还伴随着抑郁和社交障碍等精神系统疾病。与之一致,作者在临床焦虑病人的外周CD4+T细胞中也观察到了类似的现象,说明CD4+T细胞线粒体的分裂是导致焦虑发生的关键步骤。

MIGA2-/-CD4+T细胞相关炎症基因和炎症性疾病进程并未发生改变,作者进而通过代谢组学分析发现MIGA2TKO小鼠表现出严重的嘌呤合成紊乱。通过阻断黄嘌呤的合成能够显着改善MIGA2TKO小鼠的焦虑症状。杏仁核作为动物体的“情绪处理中心”,其异常的活化会导致焦虑的发生。组织病例分析显示,MIGA2TKO小鼠或者黄嘌呤处理的野生型小鼠的左侧杏仁核都表现出血管扩张和神经元的活化。单细胞转录分析揭示该区域的少突胶质细胞异常增多,而去除CD4+T细胞后则恢复正常。BrdU检测进一步提示,注射了黄嘌呤小鼠的杏仁核中的少突胶质细胞大量进入细胞周期,表现出增殖的特性。说明T细胞来源的黄嘌呤特异性地促进杏仁核区域的少突胶质细胞活化和增殖。作者也利用少突细胞特异性的启动子驱动的shRNA证明嘌呤受体AdorA1介导了该过程。在T细胞产生黄嘌呤的机制方面,作者利用代谢组学和转录组分析表明,CD4+T细胞中线粒体碎裂可导致关键转录因子IRF1累积,IRF1在Ada、Xdh和Pnp2等基因启动子区富集,使葡萄糖代谢更多的通过戊糖磷酸途径,促进嘌呤从头合成。

该研究成果确定了慢性应激如何影响外周CD4+T细胞的线粒体形态,进而诱导产生的焦虑行为中的分子机制。临床治疗精神疾病的大多数药物直接针对中枢神经系统,如选择性单胺神经递质再摄取抑制剂。这些药物伴随着许多副作用,包括性功能障碍、全身代谢紊乱和持续性高血压等。而靶向其他系统干预精神疾病的药物或治疗手段有限。该工作加深对神经发育、精神疾病与免疫生理功能之间联系的理解,对了解抑郁症和焦虑症的发病机制并开发新的治疗药物具有重要意义。

值得一提的是,在同期,哈佛医学院免疫系Jun R. Huh发表了Preview文章The Immune-Mind Connection。

“迄今为止开发的大多数治疗焦虑症或抑郁症的药物主要通过调控神经递质来调节大脑的神经功能,但这些药物并不对所有的病人有效。”哈佛医学院的研究者Saiyu Hang和Jun R. Huh评论到: “在未来对CD4+T细胞介导产生焦虑的研究中,肠道微生物的调节作用将是一个重要的研究方向。”“作者的这项工作阐明了通过靶向药物抑制CD4+T细胞黄嘌呤合成,从而对中枢神经系统的神经回路功能进行调节的可能性。为那些因免疫系统失调而导致精神疾病症状的患者提供了精准治疗设计的方向。”

据悉,靳津课题组博士研究生范柯琪与李异媛博士为文章的共同第一作者;浙江大学靳津教授与东南大学柴人杰教授为该论文的共同通讯作者。

原始出处:
Ke-qi Fan ,Yi-yuan Li ,Hao-li Wang,et al.Stress-Induced Metabolic Disorder in Peripheral CD4+ T Cells Leads to Anxiety-like Behavior.cell.Volume 179, ISSUE 4, P864-879.e19, October 31, 2019DOI:https://doi.org/10.1016/j.cell.2019.10.001

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    2020-04-10 xuyu
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    2020-01-31 维他命
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    2019-12-24 qidongfanjian
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    2019-11-01 明天jing

    焦虑是当年年轻人的共同问题,需要认真对待。

    0

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    2019-11-01 Dr Z

    学习了

    0

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