Wang Haiyang, Liu Lanxiang, Chen Xueyi, Zhou Chanjuan, Rao Xuechen, Li Wenxia, Li Wenwen, Liu Yiyun, Fang Liang, Zhang Hongmei, Song Jinlin, Ji Ping, Xie Peng
Key Laboratory of Psychoseomadsy, Stomatological Hospital of Chongqing Medical University, Chongqing, China.
College of Stomatology and Affiliated Stomatological Hospital of Chongqing Medical University, Chongqing, China.
Front Psychiatry. 2022 Apr 5;13:824209. doi: 10.3389/fpsyt.2022.824209. eCollection 2022.
Accumulating evidence indicates an important role for microRNA (miRNA)-messenger RNA (mRNA) regulatory networks in human depression. However, the mechanisms by which these networks act are complex and remain poorly understood. We used data mining to identify differentially expressed miRNAs from GSE81152 and GSE152267 datasets, and differentially expressed mRNAs were identified from the Netherlands Study of Depression and Anxiety, the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program, and the Janssen-Brain Resource Company study. We constructed a miRNA-mRNA regulatory network based on differentially expressed mRNAs that intersected with target genes of differentially expressed miRNAs, and then performed bioinformatics analysis of the network. The key candidate genes were assessed in the prefrontal cortex of chronic social defeat stress (CSDS) depression mice by quantitative real-time polymerase chain reaction (qRT-PCR). Three differentially expressed miRNAs were commonly identified across the two datasets, and 119 intersecting differentially expressed mRNAs were identified. A miRNA-mRNA regulatory network including these three key differentially expressed miRNAs and 119 intersecting differentially expressed mRNAs was constructed. Functional analysis of the intersecting differentially expressed mRNAs revealed that an abnormal inflammatory response characterized by disturbed T-helper cell 17 (Th17) differentiation was the primary altered biological function. qRT-PCR validated the decreased expression of Th17 cell differentiation-related genes, including , and β, and the increased expression of retinoic acid receptor-related orphan receptor gamma-t (γ) in CSDS mice, which showed significant depressive- and anxiety-like behaviors. This study indicates that an abnormal inflammatory response characterized by disturbed Th17 cell differentiation is the primary altered biological process in major depressive disorder. Our findings indicate possible biomarkers and treatment targets and provide novel clues to understand the pathogenesis of major depressive disorder.
越来越多的证据表明，微小RNA（miRNA）-信使核糖核酸（mRNA）调控网络在人类抑郁症中发挥着重要作用。然而，这些网络的作用机制复杂，仍知之甚少。我们通过数据挖掘从GSE81152和GSE152267数据集中鉴定出差异表达的miRNA，并从荷兰抑郁症与焦虑症研究、葛兰素史克高通量疾病特异性靶点鉴定项目以及杨森脑资源公司的研究中鉴定出差异表达的mRNA。我们基于与差异表达miRNA的靶基因相交的差异表达mRNA构建了一个miRNA-mRNA调控网络，然后对该网络进行生物信息学分析。通过定量实时聚合酶链反应（qRT-PCR）在慢性社会挫败应激（CSDS）抑郁小鼠的前额叶皮层中评估关键候选基因。在两个数据集中共同鉴定出三个差异表达的miRNA，并鉴定出119个相交的差异表达mRNA。构建了一个包含这三个关键差异表达miRNA和119个相交差异表达mRNA的miRNA-mRNA调控网络。对相交的差异表达mRNA的功能分析表明，以辅助性T细胞17（Th17）分化紊乱为特征的异常炎症反应是主要改变的生物学功能。qRT-PCR验证了CSDS小鼠中Th17细胞分化相关基因（包括 、 和β）的表达降低，以及维甲酸受体相关孤儿受体γ-t（γ）的表达增加，这些小鼠表现出明显的抑郁和焦虑样行为。这项研究表明，以Th17细胞分化紊乱为特征的异常炎症反应是重度抑郁症中主要改变的生物学过程。我们的研究结果表明了可能的生物标志物和治疗靶点，并为理解重度抑郁症的发病机制提供了新线索。
