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

Figures & data

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.

Table 1 Evaluated Cytokines, Soluble Cytokine Receptors, IRS and CIRS-Related Profiles, and IRS vs CIRS Activity Ratios

Evaluated Indices	IRS, CIRS, IRS vs CIRS Function	Controls			MDD			p-value
		Total^a (N=60)	Females^b (N=32)	Males^c (N=28)	Total^d (N=100)	Females^e (N=60)	Males^f (N=40)	a vs d	b vs e	c vs f	e vs f
Cytokines
IL-1α (pg/mL)	IRS	0.26 (0.19–0.35)	0.27 (0.20–0.35)	0.25 (0.18–0.33)	0.26 (0.19–0.40)	0.25 (0.19–0.33)	0.26 (0.21–0.51)	0.774	0.531	0.278	0.229
IL-1β (pg/mL)	IRS	1.17 (0.87–1.93)	1.39 (0.96–2.12)	1.09 (0.80–1.81)	1.37 (1.00–2.04)	1.41 (1.02–2.17)	1.21 (0.98–1.69)	0.237	0.517	0.428	0.216
IL-2 (pg/mL)	IRS	2.50 (1.50–5.22)	2.88 (1.73–5.26)	2.22 (1.41–3.31)	2.34 (1.60–4.06)	2.60 (1.82–4.06)	1.98 (1.49–3.93)	0.880	0.612	0.945	0.195
IL-4 (pg/mL)	CIRS	2.08 (1.84–2.73)	2.29 (1.87–2.79)	1.98 (1.80–2.41)	2.34 (2.02–2.67)	2.33 (2.01–2.82)	2.36 (2.07–2.63)	0.046	0.354	0.044	0.827
IL-6 (pg/mL)	IRS	0.79 (0.63–1.24)	0.84 (0.69–1.29)	0.69 (0.57–1.14)	0.92 (0.69–1.19)	0.98 (0.76–1.31)	0.88 (0.63–1.07)	0.319	0.594	0.345	0.132
IL-8 (pg/mL)	IRS	3.99 (3.04–5.91)	3.89 (2.83–5.91)	4.05 (3.59–5.58)	3.31 (2.58–5.21)	3.47 (2.51–5.10)	3.22 (2.63–5.38)	0.087	0.319	0.126	0.872
IL-10 (pg/mL)	CIRS	0.77 (0.58–0.99)	0.79 (0.64–0.94)	0.70 (0.54–1.02)	0.95 (0.70–1.44)	0.99 (0.68–1.49)	0.94 (0.73–1.31)	<0.001	0.017	0.007	0.952
IFN-γ (pg/mL)	IRS	0.42 (0.28–0.56)	0.46 (0.31–0.66)	0.34 (0.21–0.53)	0.45 (0.30–0.79)	0.44 (0.28–0.82)	0.45 (0.31–0.76)	0.161	0.993	0.052	0.759
TNF-α (pg/mL)	IRS	2.46 (2.00–2.96)	2.29 (1.78–2.83)	2.74 (2.21–3.14)	2.89 (2.29–3.42)	2.84 (2.16–3.19)	3.12 (2.63–3.47)	0.002	0.006	0.074	0.064
Soluble cytokine receptors
sIL-6R (ng/mL)	IRS	0.91 (0.52–1.42)	0.98 (0.57–1.58)	0.90 (0.46–1.36)	1.33 (0.87–1.80)	1.34 (0.91–1.81)	1.32 (0.65–1.79)	0.004	0.062	0.035	0.616
sTNF-R1 (ng/mL)	CIRS	0.48 (0.39–0.59)	0.42 (0.37–0.55)	0.54 (0.44–0.69)	0.49 (0.44–0.57)	0.48 (0.42–0.55)	0.51 (0.47–0.63)	0.400	0.198	0.956	0.015
sTNF-R2 (ng/mL)	CIRS	0.44 (0.23–0.69)	0.38 (0.22–0.69)	0.48 (0.27–0.69)	0.54 (0.38–0.73)	0.52 (0.37–0.70)	0.59 (0.47–0.77)	0.065	0.178	0.177	0.156
Profiles
IL-6 trans signaling	IRS	−0.20±0.23	−0.27±0.21	−0.10±0.49	0.23±0.20	0.43±0.27	−0.08±0.28	0.304	0.656	0.998	0.997
M1 signaling	IRS	−0.52 (−2.17–1.36)	−0.42 (−1.76–1.59)	−1.80 (−2.32–0.22)	0.06 (−1.52–1.43)	0.24 (−1.35–1.85)	−0.11 (−1.51–1.09)	0.054	0.309	0.086	0.421
Th1 profile	IRS	−0.03±0.23	0.39±0.30	−0.47±0.34	0.04±0.16	0.07±0.21	−0.01±0.24	0.800	0.998	0.997	0.996
Treg+Th2	CIRS	−0.36 (−1.34–0.24)	−0.17 (−1.09–0.53)	−0.74 (−1.74– − 0.23)	0.28 (−0.80–1.21)	0.22 (−0.97–1.33)	0.28 (−0.54–0.80)	<0.001	0.074	<0.001	0.549
allIRS	IRS	−1.04±0.46	−0.38±0.56	−1.80±0.74	0.17±0.36	0.43±0.48	−0.21±0.55	0.045	0.996	0.449	0.998
allCIRS	CIRS	−0.57±0.25	−0.56±0.35	−0.58±0.37	0.30±0.15	0.22±0.20	0.41±0.23	0.002	0.230	0.111	0.997
Ratios
TNF-α/sTNF-Rs	IRS vs CIRS	−0.53±0.24	−0.46±0.33	−0.62±0.34	0.05±0.14	0.12±0.17	−0.05±0.23	0.029	0.598	0.852	0.998
TNF-α/sTNF-R1	IRS vs CIRS	−0.19 (−0.58–0.38)	0.03 (−0.45–0.72)	−0.47 (−0.75− −0.09)	0.04 (−0.48–0.48)	−0.01 (−0.36−0.49)	0.07 (−0.58–0.48)	0.159	0.970	0.047	0.823
TNF-α/sTNF-R2	IRS vs CIRS	0.06±0.17	0.03±0.25	0.09±0.23	0.16±0.09	0.12±0.12	0.23±0.14	0.523	0.979	0.958	0.950
Th1/Th2	IRS vs CIRS	−0.15 (−1.05–0.99)	0.47 (−1.03–1.23)	−0.23 (−1.18–0.68)	−0.36 (−1.23–0.69)	−0.27 (−0.94–0.70)	−0.44 (−1.23–0.67)	0.496	0.369	0.958	0.998
Th1/Treg	IRS vs CIRS	0.28±0.21	0.67±0.32	−0.15±0.25	−0.18±0.13	−0.11±0.17	−0.28±0.22	0.051	0.085	0.996	0.998
Th1/Treg+Th2	IRS vs CIRS	0.10 (−0.73–1.40)	0.57 (−0.77–1.51)	−0.03 (−0.69–0.74)	−0.49 (−0.73–1.40)	−0.48 (−1.25–0.60)	−0.61 (−1.24–0.78)	0.011	0.053	0.076	0.784
M1/Th2	IRS vs CIRS	−0.52±0.31	−0.42±0.37	−0.63±0.52	−0.04±0.21	0.24±0.27	−0.47±0.34	0.268	0.997	0.998	0.729
M1/Treg	IRS vs CIRS	0.03±0.30	0.18±0.35	−0.17±0.53	0.18±0.22	0.30±0.27	−0.01±0.37	0.710	0.995	0.992	0.998
M1/Treg+Th2	IRS vs CIRS	0.11±0.30	0.00±0.32	−0.22±0.48	0.01±0.20	0.09±0.26	−0.28±0.28	0.973	0.998	0.997	0.998
allIRS/allCIRS	IRS vs CIRS	−0.48±0.38	0.04±0.50	−1.13±0.54	−0.35±0.33	0.30±0.43	−1.27±0.47	0.908	0.998	0.998	0.072

Notes: Values are expressed as mean±SEM for Gaussian-distributed data and as median (interquartile ranges) for non-Gaussian distributed data. p-value ≤ 0.05 (in bold) is considered statistically significant. ^aControl group; ^bControl adolescent females; ^cControl adolescent males; ^dDepressive group; ^eDepressive adolescent females; ^fDepressive adolescent males.

Abbreviations: IRS, inflammatory response system; CIRS, compensatory immune response system; MDD, major depressive disorder; IL, interleukin; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; sIL-6R, soluble interleukin-6 receptor; sTNF-R1, soluble tumor necrosis factor receptor 1; sTNF-R2, soluble tumor necrosis factor receptor 2; M1, macrophages M1; Th1, T helper cells 1; Treg, T regulatory cells; Th2, T helper cells 2; allIRS, all indices involved in the adolescent depression-linked inflammatory response system; allCIRS, all indices involved in the compensatory immune response system; sTNF-Rs, soluble tumor necrosis factor receptors (ie sTNF-R1+sTNF-R2).

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.