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

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2022 Oct 28

PMID 36303711

Authors

Nikola Ferencova

Zuzana Visnovcova

Igor Ondrejka

Dana Funakova

Igor Hrtanek

Simona Kelcikova

Ingrid Tonhajzerova

Affiliations

Soon will be listed here.

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.

Citing Articles

Investigating the relationship between inflammatory cytokines and adolescent depression: a comparative analysis.

Liu M, Tang J, Xu G, Chen X, Fang K, He F Front Psychiatry. 2025; 16:1524015.

PMID: 39980978 PMC: 11839723. DOI: 10.3389/fpsyt.2025.1524015.

Associations of pro-inflammatory factors and IL-10 levels with degree of suicide risk in adolescents with depression.

Liu W, Zheng H, Wen X, Liu L, Yang Y, Zhong H Front Psychiatry. 2025; 15:1491555.

PMID: 39882160 PMC: 11774840. DOI: 10.3389/fpsyt.2024.1491555.

Navigating the Neuroimmunomodulation Frontier: Pioneering Approaches and Promising Horizons-A Comprehensive Review.

Krsek A, Ostojic L, Zivalj D, Baticic L Int J Mol Sci. 2024; 25(17).

PMID: 39273641 PMC: 11396210. DOI: 10.3390/ijms25179695.

Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression.

Strekalova T, Radford-Smith D, Dunstan I, Gorlova A, Svirin E, Sheveleva E Neurobiol Stress. 2024; 31:100646.

PMID: 38912378 PMC: 11190747. DOI: 10.1016/j.ynstr.2024.100646.

The roles of Th cells in myocardial infarction.

Liu J, Liu F, Liang T, Zhou Y, Su X, Li X Cell Death Discov. 2024; 10(1):287.

PMID: 38879568 PMC: 11180143. DOI: 10.1038/s41420-024-02064-6.

References

Kim J, Kim J, Chang K . Sex Difference in Peripheral Inflammatory Biomarkers in Drug-Naïve Patients with Major Depression in Young Adulthood. Biomedicines. 2021; 9(7). PMC: 8301344. DOI: 10.3390/biomedicines9070708. View

Muller N, Schwarz M . The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007; 12(11):988-1000. DOI: 10.1038/sj.mp.4002006. View

Udina M, Moreno-Espana J, Navines R, Gimenez D, Langohr K, Gratacos M . Serotonin and interleukin-6: the role of genetic polymorphisms in IFN-induced neuropsychiatric symptoms. Psychoneuroendocrinology. 2013; 38(9):1803-13. DOI: 10.1016/j.psyneuen.2013.03.007. View

Debnath M, Berk M, Maes M . Translational evidence for the Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS) and neuroprogression theory of major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021; 111:110343. DOI: 10.1016/j.pnpbp.2021.110343. View

Gimeno D, Kivimaki M, Brunner E, Elovainio M, De Vogli R, Steptoe A . Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med. 2008; 39(3):413-23. PMC: 2788760. DOI: 10.1017/S0033291708003723. View

Halder I, Marsland A, Cheong J, Muldoon M, Ferrell R, Manuck S . Polymorphisms in the CRP gene moderate an association between depressive symptoms and circulating levels of C-reactive protein. Brain Behav Immun. 2009; 24(1):160-7. PMC: 3074460. DOI: 10.1016/j.bbi.2009.09.014. View

Hurst S, Wilkinson T, McLoughlin R, Jones S, Horiuchi S, Yamamoto N . Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 2001; 14(6):705-14. DOI: 10.1016/s1074-7613(01)00151-0. View

Sowa-Kucma M, Styczen K, Siwek M, Misztak P, Nowak R, Dudek D . Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts. Prog Neuropsychopharmacol Biol Psychiatry. 2017; 81:372-383. DOI: 10.1016/j.pnpbp.2017.08.024. View

Bremmer M, Beekman A, Deeg D, Penninx B, Dik M, Hack C . Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord. 2007; 106(3):249-55. DOI: 10.1016/j.jad.2007.07.002. View

10.

Shames R . Gender differences in the development and function of the immune system. J Adolesc Health. 2002; 30(4 Suppl):59-70. DOI: 10.1016/s1054-139x(01)00382-2. View

11.

Xing E, Billi A, Gudjonsson J . Sex Bias and Autoimmune Diseases. J Invest Dermatol. 2021; 142(3 Pt B):857-866. DOI: 10.1016/j.jid.2021.06.008. View

12.

Cerri A, Arosio B, Viazzoli C, Confalonieri R, Teruzzi F, Annoni G . -308(G/A) TNF-alpha gene polymorphism and risk of depression late in the life. Arch Gerontol Geriatr. 2009; 49 Suppl 1:29-34. DOI: 10.1016/j.archger.2009.09.009. View

13.

Demircan F, Gozel N, Kilinc F, Ulu R, Atmaca M . The Impact of Red Blood Cell Distribution Width and Neutrophil/Lymphocyte Ratio on the Diagnosis of Major Depressive Disorder. Neurol Ther. 2015; 5(1):27-33. PMC: 4919129. DOI: 10.1007/s40120-015-0039-8. View

14.

Gabbay V, Klein R, Alonso C, Babb J, Nishawala M, De Jesus G . Immune system dysregulation in adolescent major depressive disorder. J Affect Disord. 2008; 115(1-2):177-82. PMC: 2770721. DOI: 10.1016/j.jad.2008.07.022. View

15.

Haapakoski R, Mathieu J, Ebmeier K, Alenius H, Kivimaki M . Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015; 49:206-15. PMC: 4566946. DOI: 10.1016/j.bbi.2015.06.001. View

16.

Mosser D, Zhang X . Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2009; 226:205-18. PMC: 2724982. DOI: 10.1111/j.1600-065X.2008.00706.x. View

17.

Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S . The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011; 1813(5):878-88. DOI: 10.1016/j.bbamcr.2011.01.034. View

18.

Koskinas J, Merkouraki P, Manesis E, Hadziyannis S . Assessment of depression in patients with chronic hepatitis: effect of interferon treatment. Dig Dis. 2003; 20(3-4):284-8. DOI: 10.1159/000067682. View

19.

Fornaro M, Martino M, Battaglia F, Colicchio S, Perugi G . Increase in IL-6 levels among major depressive disorder patients after a 6-week treatment with duloxetine 60 mg/day: a preliminary observation. Neuropsychiatr Dis Treat. 2011; 7:51-6. PMC: 3056173. DOI: 10.2147/NDT.S16382. View

20.

Menter A, Augustin M, Signorovitch J, Yu A, Wu E, Gupta S . The effect of adalimumab on reducing depression symptoms in patients with moderate to severe psoriasis: a randomized clinical trial. J Am Acad Dermatol. 2010; 62(5):812-8. DOI: 10.1016/j.jaad.2009.07.022. View