MicroRNA-Messenger RNA Regulatory Network Mediates Disrupted TH17 Cell Differentiation in Depression

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 interleukin (IL)17A, IL21, IL22, and IL1β, and the increased expression of retinoic acid receptor-related orphan receptor gamma-t (RORγt) 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.