Pro-inflammatory Monocyte Phenotype and Cell-Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder

Abstract

Several lines of evidence have strongly implicated inflammatory processes in the pathobiology of major depressive disorder (MDD). However, the cellular origin of inflammatory signals and their specificity remain unclear. We examined the phenotype and glucocorticoid signaling in key cell populations of the innate immune system (monocytes) vs. adaptive immunity (T cells) in a sample of 35 well-characterized, antidepressant-free patients with MDD and 35 healthy controls individually matched for age, sex, smoking status and body mass index. Monocyte and T cell phenotype was assessed by flow cytometry. Cell-specific steroid signaling was determined by mRNA expression of pre-receptor regulation (11β-hydroxysteroid dehydrogenase type 1; 11β -HSD1), steroid receptor expression [glucocorticoid receptor (GR) and mineralocorticoid receptor (MR)], and the downstream target glucocorticoid-induced leucine-zipper (GILZ). We also collected salivary cortisol samples (8:00 a.m. and 10:00 p.m.) on two consecutive days. Patients showed a shift toward a pro-inflammatory phenotype characterized by higher frequency and higher absolute numbers of non-classical monocytes. No group differences were observed in major T cell subset frequencies and phenotype. Correspondingly, gene expression indicative of steroid resistance (i.e., lower expression of GR and GILZ) in patients with MDD was specific to monocytes and not observed in T cells. Monocyte phenotype and steroid receptor expression was not related to cortisol levels or serum levels of IL-6, IL-1β, or TNF-α. Our results thus suggest that in MDD, cells of the innate and adaptive immune system are differentially affected with shifts in monocyte subsets and lower expression of steroid signaling related genes.

Abnormal Distribution and Function of Circulating Monocytes and Enhanced Bacterial Translocation in Major Depressive Disorder

“…The differences in methodology and study populations may explain the observed discrepancies between earlier and current studies. Using a similar experimental methodology, our observations of the expansion and retraction of the intermediate monocytes and classical monocytes in MDD patients agree with recently published results (37). Furthermore, the percentage of nonclassical monocytes is normal in MDD patients.…”

“…Conflicting results regarding the classical and nonclassical monocyte subset frequencies have been previously described in MDD patients (25, 28, 29, 37). The differences in methodology and study populations may explain the observed discrepancies between earlier and current studies.…”

Depression and the risk of rheumatoid arthritis

“…1). Immune alterations, such as a reduction in the frequency of classical monocytes, and an increase in nonclassical monocytes [10], are hypothesized to be a result of neurotoxic processes occurring in response to stress in morphologically altered brains, mediated by dysregulation of the hypothalamic-pituitary-adrenal axis and a positive inflammation feedback loop [9 ▪▪ ]. Cell-mediated immune cytokines are increased, activating indoleamine 2,3-dioxygenase.…”

Peripheral Blood Cell–Stratified Subgroups of Inflamed Depression

“…Depression has been reproducibly associated with leukocytosis, increased neutrophil-to-lymphocyte ratio, and increased ratio of CD4 1 to CD8 1 T cells (19)(20)(21). However, there are less consistent results concerning regulatory T cells, T-helper 17 cells, natural killer (NK) cells, monocytes, and B cells (12)(13)(14)(15)(16)18,22). Other psychiatric disorders, including schizophrenia, bipolar disorder, and autism, have also been associated with altered cell counts (23)(24)(25).…”