Dysregulation of the TLR4/MyD88/NF‐κB Signaling Pathway and Pro‐Inflammatory Cytokines in First‐Episode Major Depressive Disorder: A Cross‐Sectional Case–Control Study

INTRODUCTION: Inflammation is increasingly recognized as a key contributor to the development and progression of major depressive disorder (MDD). This case-control study aims to assess the expression of inflammatory pathway components (TRIF, MyD88, NF-κB) and serum levels of TNF-α and IL-6 in remitted and untreated MDD patients compared to healthy controls. METHODS: This study included 150 participants: 50 newly diagnosed and untreated MDD patients, 50 MDD patients who achieved complete clinical remission following at least 8 weeks of continuous TCA treatment (TCA remitters), and 50 matched healthy controls. MDD diagnosis was based on DSM-V criteria and Beck Depression Inventory (BDI). Peripheral blood samples were collected to isolate serum and PBMCs. mRNA expression of NF-κB, TRIF, and MyD88 was quantified by qRT-PCR, while serum levels of TNF-α and IL-6 were measured using ELISA. Data were analyzed using one-way ANOVA with Tukey's post hoc test, considering p < 0.05 as statistically significant. RESULTS: No significant differences were found in age or gender among the three groups, confirming demographic comparability. BDI scores were markedly higher in both untreated and remitted MDD patients compared to controls, with untreated patients showing the most severe symptoms. Gene expression analysis revealed a significant upregulation of MYD88 (~5-fold) and NF-κB (~2.5-fold) in untreated MDD patients compared to controls (p < 0.001); treated patients also showed higher expression, though to a lesser extent. TRIF expression was higher in treated patients, but not significantly. Serum levels of TNF-α and IL-6 were significantly higher in untreated MDD patients versus controls (p < 0.001); IL-6 and TNF-α levels were also higher in treated patients but significantly lower than in the untreated group. CONCLUSION: The results support the hypothesis of a link between immune dysregulation and MDD. However, further human studies are necessary to validate the findings of the present study.