Antidepressants Improve Negative Regulation of Toll-Like Receptor Signaling in Monocytes from Patients with Major Depression

Abstract

Objective: Changes in the brain’s inflammatory status can lead to psychopathological responses, especially depression. Using animal models, recent studies have revealed that this pathology is due, in part, to innate immune responses of monocytes. Methods: We focus on the involvement of Toll-like receptors (TLRs) and expression of genes encoding their negative regulators, SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2, and TNFAIP3, in CD14⁺ monocytes from 34 patients with major depressive disorder (MDD) and 33 healthy controls before and after treatment with antidepressants. We also seek to investigate their association with depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). Results: mRNA expression of all TLRs, except TLR3 and -5, was significantly higher in monocytes from patients with MDD than in those from controls. Conversely, the “brakes” in TLR signaling, including TOLLIP, MyD88s, NOD2, and TNFAIP3, were downregulated. In clinical findings, the remission group showed higher baseline TLR4 and lower baseline IRAK3 mRNA levels but only baseline elevated SOCS1 mRNA levels, which were inversely correlated with HAMD-17 scores, predicting worsened outcome in MDD patients. In addition, TNFAIP3 mRNA levels were increased by antidepressant treatment. Conclusion: Collectively, our findings suggest a role for dysregulation of TLR signaling in monocytes in MDD and identify a balancing effect of antidepressants on this dysregulation.

NF-κB mediates lipopolysaccharide-induced alternative pre-mRNA splicing of MyD88 in mouse macrophages

“…For example, MyD88-S was increased in monocytes from septic patients and may contribute to the depressed TNF production in these patient cells (25). MyD88-S levels were decreased in monocytes from patients with major depressive disorder, and the authors suggest that this contributes to chronic low-grade inflammation present in these patients (31). MyD88-S also is reported to be increased in stimulated T-cells obtained from patients with COPD (28).…”

“…While it is generally assumed that MyD88-S is produced by an alternative pre-mRNA splicing mechanism, there are other possible explanations for its LPSmediated induction. Confounding this issue is the fact that most studies reporting on MyD88-S production in different disease contexts only monitor the production of this single isoform [see for example (25,27,28,31,32)]. Moreover, the mechanisms regulating LPS-induced MyD88-S production have not been determined.…”

SIGIRR and TNFAIP3 Are Differentially Expressed in Both PBMC and TNF-α Secreting Cells of Patients With Major Depressive Disorder

“…Previously, lower SIGIRR was found in PBMC in patients with MDD, but not statistically significant ( 14 ). In another study analyzing SIGIRR in monocyte sample of patients of MDD, significantly higher level of SIGIRR was found ( 16 ). We speculate that the lower SIGIRR in PBMC and TNF-α secreting cells indicate a deficiency to prevent TLR inflammation.…”

“…TNFAIP3 is a potent regulator of dendritic spine remodeling and synapse efficacy in neurons ( 19 ). TNFAIP3 had been investigated in various samples from patients of MDD in the past, including PBMC, monocytes, and TNF-α secreting cells ( 14 , 16 , 17 ). In this finding, we found significantly lower TNFAIP3 mRNA level in patients with MDD, which was in line with earlier studies on PBMC ( 14 ) and monocytes ( 16 ).…”

“…Earlier studies regarding TLR expressions and their negative regulators used peripheral blood mononuclear cells (PBMC) as the analyzed sample ( 14 ), which contain a variety of cells. Recent advances in technology allowed isolation of specific types of cells, such as monocytes ( 16 ) and TNF-α secreting cells ( 17 ). As mentioned earlier, TNF-α is an important cytokine in MDD ( 9 ).…”