The role of monocyte phenotype and steroid-related gene expression in major depressive disorder

Background: Inflammation has been associated with major depressive disorder (MDD). Meta-analytic evidence has shown increased levels of circulating pro-inflammatory cytokines in groups of patients with MDD. However, little is known about the cellular source of these inflammatory signals. Recent studies have suggested that innate and adaptive immunity may be differentially affected in MDD. Neuroendocrine pathways tightly regulate cellular inflammation via glucocorticoids, such as cortisol. While some studies have found neuroendocrine disturbances in MDD, it has remained unclear whether impairments in glucocorticoid signalling are cell-specific. Therefore, we interrogated phenotype and glucocorticoid signalling of key innate (monocytes) and adaptive (T cells) immune cell populations in patients with MDD and healthy controls (HC). Methods: 35 well-characterized antidepressant-free patients with MDD and HC individually matched for age, sex, smoking status and body mass index were enrolled. All participants were free of immunomodulatory medications or significant medical illness and non-pregnant. Immunophenotyping was performed by flow cytometry following established guidelines. Cell-specific steroid signalling was determined by mRNA expression of pre-receptor regulation (11β-hydroxysteroid dehydrogenase type 1 [11β-HSD1]), receptor expression (glucocorticoid [GR] and mineralocorticoid receptor [MR]), and its main downstream target (glucocorticoid-induced leucine-zipper [GILZ]). Salivary cortisol (collected on two consecutive days at 8 a.m. and 10 p.m.) and serum levels of IL-6, IL-1ß and TNF-α were analysed with ELISA. Paired-samples t-tests were used for continuous variables and McNemar’s Test for dichotomous variables. Repeated-measures ANOVA was used for cortisol values. Effects sizes were calculated as Hedges’ g. Results: In patients with MDD, we observed a shift in monocyte repertoire towards elevated frequencies of non-classical monocytes (p 0.05). Furthermore, monocytes but not T cells from patients with MDD showed lower expression of GR (p = 0.018; Hedges’g = 0.21) and GILZ (p = 0.045; Hedges’g = 0.39), indicative of steroid resistance. Finally, altered monocyte phenotype and steroid gene expression occurred against the backdrop of unchanged salivary cortisol (p = 0.32) and serum cytokine levels (ps > 0.05). Conclusion: Our results suggest that in MDD regulatory mechanisms of inflammation are affected in a cell-specific manner. More specifically, we found a shift towards a pro-inflammatory phenotype and gene expression consistent with steroid resistance that was restricted to monocytes and occurred without neuroendocrine alterations. Our results could outline avenues for tailored cell-specific treatments to target aberrant inflammation in MDD.Entzündliche Prozesse stehen mit der Pathophysiologie von Depression (MDD) in Verbindung. Meta-Analysen deuten auf erhöhte Spiegel von zirkulierenden pro-inflammatorischen Zytokinen in Patientengruppen hin. Bisher ist nur wenig über den zellulären Ursprung dieser entzündlichen Signale bekannt. Jüngere Untersuchungen konnten zeigen, dass adaptive und angeborene Immunität bei MDD differentiell beeinträchtigt sein könnte. Glukokortikoide wie Cortisol sind potente neuroendokrine Regulatoren von Inflammation. Eine veränderte neuroendokrine Regulation ist bei Patienten mit MDD beschrieben worden, allerdings ist unklar, ob diese neuroendokrinen Veränderungen zell-spezifisch auftreten. Das Ziel dieser Arbeit ist es, Phänotyp sowie Steroidregulation von Monozyten und T-Zellen, den wichtigsten Zellpopulationen von angeborenem und erworbenem Immunsystem, bei Patienten mit MDD und gesunden Kontrollen (GK) zu untersuchen. Methoden: 35 Antidepressiva-unmedizierte Patienten mit MDD und 35 GK (individuell parallelisiert nach Alter, Geschlecht, Raucherstatus und Body-Mass-Index) wurden für die Studie rekrutiert. Alle Probanden waren frei von immunmodulatorischer Medikation, ohne signifikante medizinische Begleiterkrankungen und nicht-schwanger. Immunophänotypisierung wurde mithilfe von Durchflusszytometrie gemäß etablierter Standards durchgeführt. Zell-spezifische Steroidregulation wurde anhand der mRNA-Expression auf Ebene von prä-Rezeptor- (11β-hydroxysteroid dehydrogenase type 1 [11β-HSD1]), Rezeptor- (Glukokortikoid- [GR] und Mineralokortikoidrezeptor [MR]) sowie post-Rezeptor-Ebene (glucocorticoid-induced leucine-zipper [GILZ]) bestimmt. Speichel-Cortisol zweier konsekutiver Tage (8:00 und 22:00 Uhr) sowie IL-6, IL-1ß und TNF-α-Serum-Spiegel wurden mittels ELISA analysiert. Kontinuierliche Variablen wurden mittels des t-Tests für verbundene Stichproben, dichotome Variablen mit McNemar’s Test und Speichel-Cortisol mit einer messwiederholten Varianzanalyse ausgewertet. Hedges’ g wurde als Maß der Effektstärke berechnet. Ergebnisse: Bei Patienten mit MDD zeigte sich eine signifikante Verschiebung des Monozyten-Repertoire hin zu einer erhöhten Frequenz von nicht-klassischen Monozyten (p 0.05). In Einklang hiermit zeigten nur Monozyten, nicht aber T-Zellen, von Patienten mit MDD geringere mRNA-Level von GR (p = 0.018; Hedges’ g = 0.21) und GILZ (p = 0.045; Hedges’ g = 0.39) als Monozyten von Kontrollen, was auf Steroidresistenz hindeutet. Diese Veränderungen waren unabhängig von Speichel-Cortisol- (p = 0.32) und Serum-Zytokin-Spiegeln (ps > 0.05). Conclusio: Unsere Ergebnisse deuten darauf hin, dass die Regulation von Inflammation bei Patienten mit MDD auf zell-spezifische Weise beeinträchtigt ist. Es zeigte sich eine Verschiebung hin zu einem pro-inflammatorischen Phänotypen gekoppelt mit einer Monozyten-spezifischen Genexpression, die mit Steroidresistenz konsistent ist. Diese Veränderungen traten bei depressiven Patienten ohne Erhöhung der Speichel-Cortisol-Spiegel auf. Diese Ergebnisse könnten Hinweise für zukünftige zell-spezifische Behandlung von entzündlichen Prozessen im Rahmen von MDD liefern

Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

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 (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-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-1 beta, or TNF-alpha. 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

Pro-inflammatory monocyte phenotype and cell-specific steroid signaling alterations in unmedicated patients with major depressive disorder

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 (11 beta-hydroxysteroid dehydrogenase type 1; 11 beta-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-1 beta, or TNF-alpha. 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

Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis—a randomized controlled trial

Background Only few aerobic exercise intervention trials specifically targeting cognitive functioning have been performed in multiple sclerosis. Objective and Methods This randomized controlled trial with 34 patients in the intervention group (IG) (mean: 38.2 years (±9.6)) and 34 patients in the control group (CG) (mean: 39.6 years (±9.7)) aimed to determine the effects of aerobic exercise on cognition in relapsing-remitting multiple sclerosis (RRMS). The primary outcome was verbal learning assessed by the verbal learning and memory test (VLMT). Patients were randomized to an IG or a waitlist CG. Patients in the IG exercised according to an individually tailored training schedule (with two to three sessions per week for 12 weeks). The primary analysis was carried out using the intention-to-treat (ITT) sample with ANCOVA adjusting for baseline scores. Results A total of 77 patients with RRMS were screened and 68 participants randomized (CG n = 34; IG n = 34). The sample comprised 68% females, had a mean age of 39 years, a mean disease duration of 6.3 years, and a mean expanded disability status scale of 1.8. No significant effects were detected in the ITT analysis for the primary endpoint VLMT or any other cognitive measures. Moreover, no significant treatment effects were observed for quality of life, fatigue, or depressive symptoms. Conclusion This study failed to demonstrate beneficial effects of aerobic exercise on cognition in RRMS. The trial was prospectively registered at clinicaltrials.gov (NCT02005237)

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

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