Toll-like receptor 4 methylation grade is linked to depressive symptom severity

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.

Microglial Inflammatory-Metabolic Pathways and Their Potential Therapeutic Implication in Major Depressive Disorder

“…More specifically, the dysregulation of TLR4 and NF-κB inflammatory processes has been suggested to be involved in MDD. TLR4 single gene polymorphisms were associated with suicide and anxiety scores in MDD patients, while methylation levels of TLR4-associated CpGs were related to the severity of depressive symptoms ( 121 , 122 ). In general, increased TLR4 expression and decreased expression of its inhibitor TNFAIP3 were associated with depressive symptoms ( 107 ).…”

Toll-like receptor 4 in the interface between neuroimmune response and behavioral alterations caused by stress

“…Recent data indicate that major depressive disorder (MDD) patients present changes in TLRs expression, or components of their signaling pathway, in blood cells [131][132][133][134][135][136][137]. TLR4 expression, for example, is increased in several MDD patients [132,134,[136][137][138].…”

“…Recent data indicate that major depressive disorder (MDD) patients present changes in TLRs expression, or components of their signaling pathway, in blood cells [131][132][133][134][135][136][137]. TLR4 expression, for example, is increased in several MDD patients [132,134,[136][137][138]. Interestingly, postmortem evaluation of TLRs in the PFC and dorsolateral PFC (DLPFC) of suicide and non-suicide depressive patients found higher levels of TLR4 mRNA and other TLRs [26,139,140].…”

Challenges in Analyzing Functional Epigenetic Data in Perspective of Adolescent Psychiatric Health

“…A rigorous method for multiple-testing comparisons should be further applied to the statistical results that is suitable for the analyzed sample size. Moreover, most of the methylation studies have been using accessible tissues such as whole blood and saliva to infer the mechanisms related to psychiatric outcomes [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…The calculated deconvolution estimates can be further used in statistical models as covariates [ 145 ] or investigated separately to determine their association with risk or exposure [ 146 ]. The most used method of the calculation of blood cell proportions is the reference-based Houseman algorithm, implemented in the minfi R package [ 15 , 137 , 147 , 148 ]. The reference data were from six adult White European males.…”