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Abstract
This study explores potential associations between the methylation of promoter-associated CpG sites of the toll-like receptor (TLR)-family, plasma levels of pro-inflammatory proteins and depressive symptoms in young female psychiatric patients. Ratings of depressive symptoms and blood samples were obtained from 92 young women seeking psychiatric care. Methylation of 32 promoter-associated CpG sites in TLR1 to TLR10 was analysed using the Illumina Infinium Methylation EPIC BeadChip. Expression levels of 91 inflammatory proteins were determined by proximity extension assay. Statistical correlations between depressive state, TLR1-10 methylation and inflammatory proteins were investigated. Four additional cohorts were studied to evaluate the generalizability of the findings. In the discovery cohort, methylation grade of cg05429895 (TLR4) in blood was inversely correlated with depressive symptoms score in young adults. After correction for multiple testing, plasma levels of macrophage inflammatory protein 1β (MIP-1β/CCL4) were associated with both TLR4 methylation and depressive symptom severity. A similar inverse association between TLR4 methylation in blood and affective symptoms score was also found in a cohort of 148 both males and females (<40 years of age) from the Danish Twin Registry. These findings were not, however, replicated in three other external cohorts; which differed from the first two cohorts by a higher age and mixed ethnicities, thus limiting the generalizability of our findings. However, TLR4 methylation inversely correlated with TLR4 mRNA expression in the Danish Twin Study indicating a functional significance of methylation at this particular CpG. Higher depression scores in young Scandinavian adults was associated with decreased methylation of TLR4 in blood.
Highlights
Major depressive disorder (MDD) is a leading contributor to the global burden of disease
Patients with chronic heart failure and MDD have elevated peripheral MIP-1β/CCL4 levels and this is DISCUSSION This study reports an inverse correlation between methylation of TLR4 and severity of depressive symptoms in a cohort of young adult women seeking psychiatric care mainly for symptoms of unipolar depression and/or anxiety, and this finding was replicated in a cohort of young adult twins
In both cohorts it was showed that a lower level of methylation of the TLR4associated CpG site cg05429895 was associated with an increased risk of suffering from more severe depressive symptoms
Summary
Major depressive disorder (MDD) is a leading contributor to the global burden of disease. The interaction between the brain and the immune system is both bi-directional and complex. Cytokines and chemokines associated with depressive states are suggested to directly execute both neuromodulatory and neurotransmitter-like effects and can regulate the HPA axis [7]. Neuroendocrine factors, such as peptide hormones, as well as their receptors, and lymphoid organs are innervated. The autonomic nerve system modulates the cytokine production via the “inflammatory reflex” and is of major importance to determine the magnitude of the inflammatory response (i.e., cytokine release from macrophages) via afferent signals from the vagal nerve to the brain. Acetylcholine interacts with nicotinic receptor α7 receptor subunit on macrophages, deactivates them and inhibits further cytokine release— dampening the inflammation [8]
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