Investigating the Role of TNF-Alpha through Blood-Brain Barrier Integrity in Stress-Induced Depression

Background: Major depressive disorder (MDD) is a complex psychiatric condition significantly impacted by environmental stress and inflammation. Previous research suggests that stress-induced alterations in the blood-brain barrier (BBB) may allow pro-inflammatory cytokines like interleukin-6 (IL-6) to enter the brain, contributing to depression. Tumor necrosis factor-alpha (TNF-α) is another prominent cytokine implicated in depression, but its role in the context of BBB integrity and stress-mediated depression remains unclear.

Objectives: This study aimed to investigate whether TNF-α plays a similar role as IL-6 in the development of depression through interactions with environmental stress and BBB integrity. Specifically, we examined the interaction between environmental stress, genetic variants of CLDN5 (the gene of the Claudin-5, a protein critical for BBB integrity), and TNF (the gene encoding the TNF-α protein) genetic variants on depressive symptoms.

Methods: We utilized data from the UK Biobank, comprising genetic, health, and lifestyle information from approximately 500,000 participants aged 40 to 69. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9) and a composite Current Depressive Symptoms (CDS) score based on self-reported questionnaire items. Environmental stress was quantified through participants' reports of significant life events in the past two years. Genetic analysis focused on 15 single nucleotide polymorphisms (SNPs) within the TNF gene (after linkage disequilibrium pruning) and a functional polymorphism in CLDN5 (rs885985). Linear regression models were used to assess main effects, gene-gene interactions, gene-environment interactions, and three-way interactions on depressive symptoms, adjusting for covariates and applying Bonferroni correction for multiple testing.

Results: No significant associations were found between TNF genetic variants and depressive symptoms after correcting for multiple testing. While some TNF SNPs showed nominal significance in interaction models - most notably rs3093546, which showed nominal significance in both depressive phenotypes - the findings were not robust enough to confirm a significant role. Unlike previous findings with IL6, TNF did not exhibit significant interactions with environmental stress and CLDN5 variants affecting depression risk.

Conclusions: The study does not support a significant role for TNF genetic variants interacting with environmental stress and BBB integrity in influencing depression risk. These findings suggest that IL-6 and BBB integrity may be more critical targets for understanding and treating stress-related depression, highlighting the complexity of depression's pathophysiology.

(Neuropsychopharmacol Hung 2024; 26(4): 197-203)