Evaluation of Inflammatory Response System (IRS) and Compensatory Immune Response System (CIRS) in Adolescent Major Depression

Abstract

Purpose: Nowadays, the role of two tightly interconnected systems, the inflammatory response system (IRS) and the compensatory immune response system (CIRS) in depression, is increasingly discussed. Various studies indicate pro-inflammatory activity in adolescent depression; however, there is an almost complete lack of findings about IRS and CIRS balance. Thus, we aimed to assess different IRS and CIRS indices, profiles, and IRS/CIRS ratios in drug-naïve MDD patients at adolescent age, with respect to sex.

Patients and methods: One hundred MDD adolescents (40 boys, average age: 15.4±1.2 yrs.) and 60 controls (28 boys, average age: 15.3±1.5 yrs.) were examined. Evaluated parameters were 1. plasma levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, tumor necrosis factor alpha (TNF-α), soluble receptor of IL-6 (sIL-6R), soluble receptors of TNF-α (sTNF-R1, sTNF-R2); 2. profiles: IL-6 trans-signaling, M1 macrophage signaling, helper T lymphocytes (Th) 1 profile, regulatory T lymphocytes (Treg)+Th2, allIRS, and allCIRS; 3. IRS vs CIRS activity ratios: TNF-α/TNF-R1, TNF-α/TNF-R2, TNF-α/sTNF-Rs (ie sTNF-R1+sTNF-R2), Th1/Th2, Th1/Treg, Th1/Th2+Treg, M1/Th2, M1/Treg, M1/Treg+Th2, allIRS/allCIRS.

Results: MDD patients showed increased IL-4, IL-10, TNF-α, sIL-6R, Treg+Th2, allIRS, allCIRS, and TNF-α/sTNF-Rs, and decreased Th1/Th2+Treg. MDD females showed increased IL-10 and TNF-α compared to control females. MDD males showed increased IL-4, IL-10, sIL-6R, Treg+Th2, and TNF-α/TNF-R1 compared to control males. Increased sTNF-R1 was found in MDD males compared to MDD females. Positive correlations were found between CDI score and sIL-6R and IL-10 in the total group and between CDI score and IL-10 in adolescent males.

Conclusion: Our study for the first time extensively evaluated IRS and CIRS interactions revealing enhanced pro-inflammatory TNF-α signaling and IL-6 trans-signaling in association with increased IL-10- and IL-4-mediated anti-inflammatory activity in first-episode depression at the adolescent age. Moreover, results reflect the sex-specific simultaneous activation of IRS and CIRS pathways in adolescent depression.

Keywords: adolescent age; comprehensive cytokine analysis; major depressive disorder; neuroimmune interactions; sex differences.

Figure 1

Simplified schematic diagram of crucial immune cells and mediators involved in inflammatory response system (IRS) and compensatory immune response system (CIRS) pathways in major depression. IRS pathway includes: 1. activated M1 macrophages releasing interleukin (IL)-1β, IL-6 associated with soluble IL-6 receptor (sIL-6R), tumor necrosis factor α (TNF-α); 2. activated T helper 1 cells (Th1) releasing IFN-γ; and 3. activated Th17 cells releasing IL-17. CIRS pathway consists of: 1. activated M2 macrophages releasing IL-10; 2. activated Th2 cells releasing IL-4; and 3. activated T regulatory (Treg) cells releasing IL-10. Other markers involved in CIRS pathway include soluble cytokine receptors (sIL-2R, sTNF-R1, sTNF-R2) and soluble IL-1 receptor antagonist (sIL-1RA). Macrophages and T-lymphocytes interplay with each other and can drive their polarization. More specifically, Th cells (Th1, Th2, Th17) drive the polarization of M0 to M1 and/or M2 macrophages. Moreover, Th1 cells bi-directionally interact with M1, while Th2 and Treg cells with M2.

Figure 2

Correlation analysis. (A) Positive correlations between depressive symptoms and sIL-6R and IL-10 in the total group; (B) Positive correlations between depressive symptoms and IL-10 in adolescent males.