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IL-17 enhanced the susceptibility to fluoxetine resistance in depression via the JAK1-STAT6 signaling pathway

ABSTRACT: This study aims at investigating the role of IL-17 in fluoxetine resistance in depression.The WGCNA analysis was utilized to analyze differentially expressed genes between response to antidepressant (GRA) group and resistance to antidepressant (AR)group. Furthermore, the treatment resistance model of depression was established inChronic unpredictable mild stress (CUMS) mice administrated with fluoxetine (widely used clinical medication for the treatment of depression) according to sucrose preference rate. Depression-like behaviors in mice were detected in Control group, CUMS group, GRA group, AR group, SR1001 (Th17 differentiation inhibitor) group. Subsequently, HT22 cells were exposed to IL-17 secreted by Th17 differentiation. Transcriptome sequencing from the Control and IL-17 group was used to screen differential genes. And then HT22 cells were transfected with si-JAK1 or si-STAT6. Th17 differentiation, the integrity of the blood-brain barrier (BBB), JAK1-STAT6 signaling pathway related proteins were detected by western blot, immunocytochemistry, flow cytometric analysis, ELISA experiments, immunofluorescence, and PCR. The inhibition of Th17 differentiation and the reduction of peripheral IL-17 release could increase their sensitivity to fluoxetine resistance and relieve the depression-like behavior. This process may be associated with the JAK1-STAT6 pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE263959 | GEO | 2025/04/13

REPOSITORIES: GEO

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Project description:Objective: To elucidate the potential effects of stressful factors for depression on the hippocampal, frontal cortex and pituitary gland genome-wide transcriptomes at the molecular level, we evaluated the transcriptomic profiles of depression rats under chronic restraint stress (CRS). Methods: Forty-eight rats were randomly divided into control, model, fluoxetine and acupuncture groups. Experimental period was 28 days. Open-field test, Sucrose preference and body weight were investigated respectively at the experiment before and after the experiment. The experiment having been finished, solexa sequencing technology (Illumina Nextseq 500/151nt) was applied to investigate and verify the altered hippocampal, frontal cortex and pituitary gland genome-wide transcriptome analysis in rats of all groups. Results: Based on the data from RNA-seq analysis, it revealed that compared the expression of genes in the control group with model group in the respective of three brain tissues, 101, 134, 148 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively; compared the expression of genes in the fluoxetine group with model group in the respective of three brain tissues, 41, 46, 87 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively; compared the expression of genes in the acupuncture group with model group in the respective of three brain tissues, 107, 89, 179 differential expression genes were found in the hippocampus, frontal cortex and pituitary gland, respectively. Furthermore, we used the GO (Gene ontology) analysis and KEGG (Kyo-To conservation of Genes and Genomes) pathway analysis for these differentially expressed genes. We found that the results of these two analyses were consistent, both mainly related to monoamine neurotransmitters, inflammation and immune response in control group VS model group. It is noted that this phenomenon also appears in fluoxetine group compared with model group, acupuncture group VS model group. Importantly, the antidepressant effect of acupuncture was more extensive, which was more consistent with the pathogenesis of depression induced by CRS in rats. Conclusions: Our study represents the first detailed analysis of the hippocampal, frontal cortex and pituitary gland genome-wide transcriptomes in depression rats under CRS by RNA-seq technology. The results of this study revealed multiple DEGs and possible mechanisms specifying the function of hippocampal, frontal cortex and pituitary gland in depression rats induced by CRS. These results provide a basis for further investigation of the signaling mechanisms that affect central nervous system output related to stress-sensitive depressive disorder development.

Project description:Major depression is a multidimensional disorder highly prevalent in modern society. Although several classes of antidepressants (ADs) are currently available to treat depression, the effectiveness of treatment is still limited, as many patients do not show full remission; thus, there is a need to find better patients’ directed therapeutic strategies. Neuroplastic changes in several brain regions, namely in the hippocampal dentate gyrus (DG), are amongst the best correlates of depression and of ADs actions. In this study the targets and molecular mediators of chronic stress and of four ADs from different pharmacological classes (fluoxetine, imipramine, tianeptine and agomelatine) were investigated in the DG. Using the unpredictable chronic mild stress (uCMS) animal model of depression, the molecular commonalities and specificities of the ADs were determined. All ADs, except agomelatine, could reverse the behavioral deficits produced by uCMS, and the neuroplastic changes in the DG; agomelatine reversed only the anhedonic profile in the sucrose consumption test. Chronic stress induced mild but relevant molecular changes that were mostly reversed by fluoxetine, imipramine and tianeptine. Fluoxetine reduced pro-inflammatory response and increased cell metabolism pathways. Its actions were mostly dependent on molecular changes occurring in neurons. Similarities were found between imipramine and tianeptine molecular actions and targets, as both activated pathways related to cellular protection. Moreover, no particular neural cell type enrichment was found with both treatments. Agomelatine presented a very dissimilar molecular pattern impacting greatly on Rho-GTPases-related pathways in oligodendrocytes and neurons. The recognition of these molecular alterations contributes to the understanding of the processes implicated in the onset and treatment of depression and may pave the way for more effective therapeutic interventions. We compared gene expresssion in the dentate gyros of rats which were either untreated, exposed to unpredictable chronic mild stress, or exposed to the same stress and treated with either fluoxetine, imipramine, tianeptine, or agomelatine

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IL-17 enhanced the susceptibility to fluoxetine resistance in depression via the JAK1-STAT6 signaling pathway

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