BACKGROUND Depression is a common mental disease that mainly manifests as bad mood, decreased interest, pessimism, slow thinking, lack of initiative, poor diet and sleep. Patients with severe depression have suicidal tendencies. Exosomes are small vesicles released by the fusion of a multivesicular body and membranes, and they contain specific proteins, nucleic acids, and lipids related to the cells from which they originate. MicroRNAs (miRNAs) are 20-24 nt RNAs that can be packaged into exosomes and can play important regulatory roles. Astrocytes are the most abundant cell population in the central nervous system and have a close link to depression. Astrocyte activation could result in the release of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, which could promote the symptoms of depression. In previous research, our team confirmed that NK cells regulate depression in mice. Here, we propose that miRNA in the exosomes from NK cells performs this antidepressant function. METHODS Exosomes from NK cells were shown by in vivo and in vitro experiments to alleviate symptoms of chronic mild stress in mice and decrease pro-inflammatory cytokines release from astrocytes. The production of pro-inflammatory cytokines was assessed by ELISA. Microarray analysis was used to identify critical miRNAs. Luciferase reporter assays, qPCR, and other experiments were used to prove that exosomal miR-207 has an important role in alleviating the symptoms of stress in mice. RESULTS MiRNA-containing exosomes from NK cells could alleviate symptoms of chronic mild stress in mice. In vivo experiments showed that these exosomes decreased the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) released by astrocytes. By microarray analysis of exosome miRNA profiles, miR-207 was found to be overexpressed in exosomes derived from unstressed mice. Experiments confirmed that miR-207 directly targets TLR4 interactor with leucine-rich repeats (Tril) and inhibits NF-κB signaling in astrocytes. MiR-207 could decrease the release of pro-inflammatory cytokines and inhibit expression of Tril in vitro. In vivo experiments revealed that exosomes with low miR-207 levels showed decreased antidepressant activity. CONCLUSION Collectively, our findings revealed that exosomal miR-207 alleviated symptoms of depression in stressed mice by targeting Tril to inhibit NF-κB signaling in astrocytes.

中文翻译：

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NK细胞衍生的外来体携带miR-207并减轻小鼠的抑郁样症状。

背景技术抑郁症是一种常见的精神疾病，主要表现为情绪低落，兴趣降低，悲观，思维缓慢，缺乏主动性，饮食和睡眠不足。重度抑郁症患者有自杀倾向。外来体是通过多囊体和膜融合释放的小囊泡，它们含有与它们起源的细胞相关的特定蛋白质，核酸和脂质。MicroRNA（miRNA）是20-24 nt的RNA，可以包装到外泌体中，并可以发挥重要的调节作用。星形胶质细胞是中枢神经系统中最丰富的细胞群，与抑郁症有着密切的联系。星形胶质细胞的激活可能导致炎性细胞因子的释放，包括IL-1β，IL-6和TNF-α，它们可以促进抑郁症的症状。在以前的研究中 我们的团队证实NK细胞可调节小鼠的抑郁症。在这里，我们建议NK细胞的外泌体中的miRNA执行此抗抑郁功能。方法体内和体外实验显示，NK细胞的外来体可减轻小鼠慢性轻度应激的症状，并减少星形胶质细胞释放的促炎细胞因子。通过ELISA评估促炎细胞因子的产生。微阵列分析用于鉴定关键的miRNA。萤光素酶报告基因检测，qPCR和其他实验被用来证明外泌体miR-207在减轻小鼠的压力症状方面具有重要作用。结果来自NK细胞的含miRNA的外泌体可以减轻小鼠慢性轻度应激的症状。体内实验表明，这些外泌体降低了促炎细胞因子（IL-1β，星形胶质细胞释放IL-6和TNF-α）。通过外泌体miRNA谱的微阵列分析，发现miR-207在无压力小鼠衍生的外泌体中过表达。实验证实，miR-207直接与富含亮氨酸的重复序列（Tril）靶向TLR4相互作用，并抑制星形胶质细胞中的NF-κB信号传导。MiR-207可以减少促炎细胞因子的释放，并在体外抑制Tril的表达。体内实验显示，miR-207水平低的外泌体显示出降低的抗抑郁活性。结论我们的发现共同表明，外泌体miR-207通过靶向Tril抑制星形胶质细胞中的NF-κB信号传导，减轻了应激小鼠的抑郁症状。发现miR-207在无压力小鼠衍生的外泌体中过表达。实验证实，miR-207直接与富含亮氨酸的重复序列（Tril）靶向TLR4相互作用，并抑制星形胶质细胞中的NF-κB信号传导。MiR-207可以减少促炎细胞因子的释放并抑制Tril的表达。体内实验显示，miR-207水平低的外泌体显示出降低的抗抑郁活性。结论我们的发现共同表明，外泌体miR-207通过靶向Tril抑制星形胶质细胞中的NF-κB信号传导，减轻了应激小鼠的抑郁症状。发现miR-207在无压力小鼠衍生的外泌体中过表达。实验证实，miR-207直接与富含亮氨酸的重复序列（Tril）靶向TLR4相互作用，并抑制星形胶质细胞中的NF-κB信号传导。MiR-207可以减少促炎细胞因子的释放，并在体外抑制Tril的表达。体内实验显示，miR-207水平低的外泌体显示出降低的抗抑郁活性。结论我们的发现共同表明，外泌体miR-207通过靶向Tril抑制星形胶质细胞中的NF-κB信号传导，减轻了应激小鼠的抑郁症状。MiR-207可以减少促炎细胞因子的释放，并在体外抑制Tril的表达。体内实验显示，miR-207水平低的外泌体显示出降低的抗抑郁活性。结论我们的发现共同表明，外泌体miR-207通过靶向Tril抑制星形胶质细胞中的NF-κB信号传导，减轻了应激小鼠的抑郁症状。MiR-207可以减少促炎细胞因子的释放，并在体外抑制Tril的表达。体内实验显示，miR-207水平低的外泌体显示出降低的抗抑郁活性。结论我们的发现共同表明，外泌体miR-207通过靶向Tril抑制星形胶质细胞中的NF-κB信号传导，减轻了应激小鼠的抑郁症状。