Prominent Role of T Cells and Inflammasome in Bipolar Disorder
Abstract
This study investigated the gene expression of t-bet, interferon-γ (IFN-γ), GATA3, interleukin-4 (IL-4), RoRγt, IL-17, Foxp3, IL-10, and transforming growth factor-β (TGF-β) as transcription factors and associated cytokines of T-cell subsets, and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), P2X7R, IL-1β, and IL-18 as inflammasome complex-related factors in bipolar disorder (BD) cases compared to healthy controls (HCs).
Whole blood was collected from 48 BD patients and 48 HCs. RNA was then extracted, cDNA was synthesized, and gene expression was assessed using SYBR® Green real-time polymerase chain reaction (PCR) with specific primers.
P2X7R expression was significantly higher in BD patients than in HCs. Additionally, GATA3 and Foxp3 expression levels were significantly lower, and IL-17 expression levels were significantly higher in BD patients than in HCs.
In conclusion, higher levels of inflammation-associated factors and a deregulated balance of T-cell subsets toward a pro-inflammatory status could highlight the importance and involvement of inflammation in the immunopathogenesis of BD.
1. Ghoryani M, Faridhosseini F, Talaei A, Faridhosseini R, Tavakkol-Afshari J, Moghaddam MD, et al. Gene expression pattern of CCL2, CCL3, and CXCL8 in patients with bipolar disorder. J Res Med Sci. 2019;24(1):45.
2. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3(2):171-8.
3. Ioannou M, Simon MS, Borkent J, Wijkhuijs A, Berghmans R, Haarman BC, Drexhage HA. Higher T central and lower effector memory cells in bipolar disorder: A differentiation abnormality? Brain Behav Immun Health. 2024;38:100764.
4. De Crescenzo F, Serra G, Maisto F, Uchida M, Woodworth H, Casini MP, et al. Suicide attempts in juvenile bipolar versus major depressive disorders: systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56(10):825-31.
5.Marangoni C, Faedda GL, Baldessarini RJ. Clinical and environmental risk factors for bipolar disorder: review of prospective studies. Harvard Rev Psychiatry. 2018;26(1):1-7.
6. Mousavizadegan S, Maroufi M. Comparison of salivary testosterone levels in different phases of bipolar I disorder and control group. J Res Med Sci. 2018;23(1):31.
7. Colpo GD, Leboyer M, Dantzer R, Trivedi MH, Teixeira AL. Immune-based strategies for mood disorders: facts and challenges. Exp Rev Neurotherapeutics. 2018;18(2):139-52.
8. Ye G, Yin GZ, Tang Z, Fu JL, Chen J, Chen SS, et al. Association between increased serum interleukin-6 levels and sustained attention deficits in patients with major depressive disorder. Psychol Med. 2018;48(15):2508-14.
9. Bai YM, Su TP, Li CT, Tsai SJ, Chen MH, Tu PC, Chiou WF. Comparison of pro‐inflammatory cytokines among patients with bipolar disorder and unipolar depression and normal controls. Bipolar Diso. 2015;17(3):269-77.
10. Goldsmith D, Rapaport M, Miller B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696-709.
11. Wang D, Wang H, Gao H, Zhang H, Zhang H, Wang Q, Sun Z. P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Bioscience. 2020;10:1-9.
12. Ozdamar Unal G, Hekimler Ozturk K, Inci HE. Increased NLRP3 inflammasome expression in peripheral blood mononuclear cells of patients with schizophrenia: a case-control study. Int J Psychiatry Clin Practice. 2023;27(2):111-7.
13. Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387-401.
14. Pietruczuk K, Lisowska KA, Grabowski K, Landowski J, Cubała WJ, Witkowski JM. Peripheral blood lymphocyte subpopulations in patients with bipolar disorder type II. Sci Rep. 2019;9(1):5869.
15. Barbosa IG, Machado-Vieira R, Soares JC, Teixeira AL. The immunology of bipolar disorder. Neuroimmunomodulation. 2014;21(2-3):117-22.
16. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann New York Academy Sci. 2019;1437(1):57-67.
17. Teixeira AL, Martins LB, Berk M, Bauer ME. Severe psychiatric disorders and general medical comorbidities: inflammation-related mechanisms and therapeutic opportunities. Clin Sci. 2022;136(17):1257-80.
18. Padmos RC, Van Baal GCM, Vonk R, Wijkhuijs AJ, Kahn RS, Nolen WA, Drexhage HA. Genetic and environmental influences on pro-inflammatory monocytes in bipolar disorder: a twin study. Archiv General psychiatry. 2009;66(9):957-65.
19.Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatric Res. 1995;29(2):141-52.
20. Kilbourne AM, Cornelius JR, Han X, Pincus HA, Shad M, Salloum I, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Dis. 2004;6(5):368-73.
21. Munkholm K, Braüner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatric Res. 2013;47(9):1119-33.
22. Goldstein BI, Fagiolini A, Houck P, Kupfer DJ. Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States. Bipolar Dis. 2009;11(6):657-62.
23. de Miranda AS, de Brito Toscano EC, O’Connor JC, Teixeira AL. Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders. Expert opinion on therapeutic targets. 2024 May 3;28(5):401-18.
24. Su W-J, Zhang T, Jiang C-L, Wang W. Clemastine alleviates depressive-like behavior through reversing the imbalance of microglia-related pro-inflammatory state in mouse hippocampus. Front Cell Neurosci. 2018;12:412.
25. Pelegrin P. P2X7 receptor and the NLRP3 inflammasome: Partners in crime. Biochem Pharmacol. 2021;187:114385.
26. García-Álvarez L, Caso J, García-Portilla M, De la Fuente-Tomás L, González-Blanco L, Martínez PS, et al. Regulation of inflammatory pathways in schizophrenia: a comparative study with bipolar disorder and healthy controls. Europ Psychiatry. 2018;47:50-9.
27. Scaini G, Barichello T, Fries GR, Kennon EA, Andrews T, Nix BR, et al. TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation. Neuropsychopharmacology. 2019;44(7):1291-9.
28. Kim HK, Andreazza AC, Elmi N, Chen W, Young LT. Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: a potential mediator between mitochondria and immune-activation. J Psychiatric Res. 2016;72:43-50.
29. Grosse L, Hoogenboezem T, Ambrée O, Bellingrath S, Jörgens S, de Wit HJ, et al. Deficiencies of the T and natural killer cell system in major depressive disorder: T regulatory cell defects are associated with inflammatory monocyte activation. Brain Behav Immun. 2016;54:38-44.
30. Fan K-q, Li Y-y, Wang H-l, Mao X-t, Guo J-x, Wang F, et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell. 2019;179(4):864-79. e19.
31. Pietruczuk K, Lisowska KA, Grabowski K, Landowski J, Witkowski JM. Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder. Sci Reports. 2018;8(1):3327.
32. Barbosa IG, Rocha NP, Assis F, Vieira ÉLM, Soares JC, Bauer ME, Teixeira AL. Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders. Int J Neuropsychopharmacol. 2015;18(1):pyu021.
33. Do Prado CH, Rizzo LB, Wieck A, Lopes RP, Teixeira AL, Grassi-Oliveira R, Bauer ME. Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology. 2013;38(5):667-76.
34. Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA, Drexhage HA. The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav Immun. 2011;25(6):1206-13.
35. Snijders G, Schiweck C, Mesman E, Grosse L, De Wit H, Nolen W, et al. A dynamic course of T cell defects in individuals at risk for mood disorders. B Brain Behav Immun. 2016;58:11-17.. 2016;58:11-7.
36. Vogels RJ, Koenders MA, Van Rossum EF, Spijker AT, Drexhage HA. T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome. Front Psychiatry. 2017;8:34.
37. Wieck A, Grassi-Oliveira R, do Prado CH, Rizzo LB, de Oliveira AS, Kommers-Molina J, et al. Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder. Brain, behavior, and immunity. 2013;34:47-55.
38. Wu W, Zheng Y-l, Tian L-p, Lai J-b, Hu C-c, Zhang P, et al. Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study. Sci Rep. 2017;7(1):40530.
39.Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, et al. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Europ J Immunol. 2008;38(7):1807-13.
40. Snijders G, Brouwer R, Kemner S, Bootsman F, Drexhage H, Hillegers M. Genetic and environmental influences on circulating NK and T cells and their relation to bipolar disorder. Int J Bipolar Dis. 2019;7:1-7.
2. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3(2):171-8.
3. Ioannou M, Simon MS, Borkent J, Wijkhuijs A, Berghmans R, Haarman BC, Drexhage HA. Higher T central and lower effector memory cells in bipolar disorder: A differentiation abnormality? Brain Behav Immun Health. 2024;38:100764.
4. De Crescenzo F, Serra G, Maisto F, Uchida M, Woodworth H, Casini MP, et al. Suicide attempts in juvenile bipolar versus major depressive disorders: systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2017;56(10):825-31.
5.Marangoni C, Faedda GL, Baldessarini RJ. Clinical and environmental risk factors for bipolar disorder: review of prospective studies. Harvard Rev Psychiatry. 2018;26(1):1-7.
6. Mousavizadegan S, Maroufi M. Comparison of salivary testosterone levels in different phases of bipolar I disorder and control group. J Res Med Sci. 2018;23(1):31.
7. Colpo GD, Leboyer M, Dantzer R, Trivedi MH, Teixeira AL. Immune-based strategies for mood disorders: facts and challenges. Exp Rev Neurotherapeutics. 2018;18(2):139-52.
8. Ye G, Yin GZ, Tang Z, Fu JL, Chen J, Chen SS, et al. Association between increased serum interleukin-6 levels and sustained attention deficits in patients with major depressive disorder. Psychol Med. 2018;48(15):2508-14.
9. Bai YM, Su TP, Li CT, Tsai SJ, Chen MH, Tu PC, Chiou WF. Comparison of pro‐inflammatory cytokines among patients with bipolar disorder and unipolar depression and normal controls. Bipolar Diso. 2015;17(3):269-77.
10. Goldsmith D, Rapaport M, Miller B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21(12):1696-709.
11. Wang D, Wang H, Gao H, Zhang H, Zhang H, Wang Q, Sun Z. P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Bioscience. 2020;10:1-9.
12. Ozdamar Unal G, Hekimler Ozturk K, Inci HE. Increased NLRP3 inflammasome expression in peripheral blood mononuclear cells of patients with schizophrenia: a case-control study. Int J Psychiatry Clin Practice. 2023;27(2):111-7.
13. Saigusa R, Winkels H, Ley K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020;17(7):387-401.
14. Pietruczuk K, Lisowska KA, Grabowski K, Landowski J, Cubała WJ, Witkowski JM. Peripheral blood lymphocyte subpopulations in patients with bipolar disorder type II. Sci Rep. 2019;9(1):5869.
15. Barbosa IG, Machado-Vieira R, Soares JC, Teixeira AL. The immunology of bipolar disorder. Neuroimmunomodulation. 2014;21(2-3):117-22.
16. Bauer ME, Teixeira AL. Inflammation in psychiatric disorders: what comes first? Ann New York Academy Sci. 2019;1437(1):57-67.
17. Teixeira AL, Martins LB, Berk M, Bauer ME. Severe psychiatric disorders and general medical comorbidities: inflammation-related mechanisms and therapeutic opportunities. Clin Sci. 2022;136(17):1257-80.
18. Padmos RC, Van Baal GCM, Vonk R, Wijkhuijs AJ, Kahn RS, Nolen WA, Drexhage HA. Genetic and environmental influences on pro-inflammatory monocytes in bipolar disorder: a twin study. Archiv General psychiatry. 2009;66(9):957-65.
19.Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatric Res. 1995;29(2):141-52.
20. Kilbourne AM, Cornelius JR, Han X, Pincus HA, Shad M, Salloum I, et al. Burden of general medical conditions among individuals with bipolar disorder. Bipolar Dis. 2004;6(5):368-73.
21. Munkholm K, Braüner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatric Res. 2013;47(9):1119-33.
22. Goldstein BI, Fagiolini A, Houck P, Kupfer DJ. Cardiovascular disease and hypertension among adults with bipolar I disorder in the United States. Bipolar Dis. 2009;11(6):657-62.
23. de Miranda AS, de Brito Toscano EC, O’Connor JC, Teixeira AL. Targeting inflammasome complexes as a novel therapeutic strategy for mood disorders. Expert opinion on therapeutic targets. 2024 May 3;28(5):401-18.
24. Su W-J, Zhang T, Jiang C-L, Wang W. Clemastine alleviates depressive-like behavior through reversing the imbalance of microglia-related pro-inflammatory state in mouse hippocampus. Front Cell Neurosci. 2018;12:412.
25. Pelegrin P. P2X7 receptor and the NLRP3 inflammasome: Partners in crime. Biochem Pharmacol. 2021;187:114385.
26. García-Álvarez L, Caso J, García-Portilla M, De la Fuente-Tomás L, González-Blanco L, Martínez PS, et al. Regulation of inflammatory pathways in schizophrenia: a comparative study with bipolar disorder and healthy controls. Europ Psychiatry. 2018;47:50-9.
27. Scaini G, Barichello T, Fries GR, Kennon EA, Andrews T, Nix BR, et al. TSPO upregulation in bipolar disorder and concomitant downregulation of mitophagic proteins and NLRP3 inflammasome activation. Neuropsychopharmacology. 2019;44(7):1291-9.
28. Kim HK, Andreazza AC, Elmi N, Chen W, Young LT. Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: a potential mediator between mitochondria and immune-activation. J Psychiatric Res. 2016;72:43-50.
29. Grosse L, Hoogenboezem T, Ambrée O, Bellingrath S, Jörgens S, de Wit HJ, et al. Deficiencies of the T and natural killer cell system in major depressive disorder: T regulatory cell defects are associated with inflammatory monocyte activation. Brain Behav Immun. 2016;54:38-44.
30. Fan K-q, Li Y-y, Wang H-l, Mao X-t, Guo J-x, Wang F, et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell. 2019;179(4):864-79. e19.
31. Pietruczuk K, Lisowska KA, Grabowski K, Landowski J, Witkowski JM. Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder. Sci Reports. 2018;8(1):3327.
32. Barbosa IG, Rocha NP, Assis F, Vieira ÉLM, Soares JC, Bauer ME, Teixeira AL. Monocyte and lymphocyte activation in bipolar disorder: a new piece in the puzzle of immune dysfunction in mood disorders. Int J Neuropsychopharmacol. 2015;18(1):pyu021.
33. Do Prado CH, Rizzo LB, Wieck A, Lopes RP, Teixeira AL, Grassi-Oliveira R, Bauer ME. Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology. 2013;38(5):667-76.
34. Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA, Drexhage HA. The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav Immun. 2011;25(6):1206-13.
35. Snijders G, Schiweck C, Mesman E, Grosse L, De Wit H, Nolen W, et al. A dynamic course of T cell defects in individuals at risk for mood disorders. B Brain Behav Immun. 2016;58:11-17.. 2016;58:11-7.
36. Vogels RJ, Koenders MA, Van Rossum EF, Spijker AT, Drexhage HA. T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome. Front Psychiatry. 2017;8:34.
37. Wieck A, Grassi-Oliveira R, do Prado CH, Rizzo LB, de Oliveira AS, Kommers-Molina J, et al. Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder. Brain, behavior, and immunity. 2013;34:47-55.
38. Wu W, Zheng Y-l, Tian L-p, Lai J-b, Hu C-c, Zhang P, et al. Circulating T lymphocyte subsets, cytokines, and immune checkpoint inhibitors in patients with bipolar II or major depression: a preliminary study. Sci Rep. 2017;7(1):40530.
39.Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, et al. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Europ J Immunol. 2008;38(7):1807-13.
40. Snijders G, Brouwer R, Kemner S, Bootsman F, Drexhage H, Hillegers M. Genetic and environmental influences on circulating NK and T cells and their relation to bipolar disorder. Int J Bipolar Dis. 2019;7:1-7.
| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Bipolar disorder Immune response Inflammation Inflammasome T-lymphocyte subsets | ||
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How to Cite
1.
Dehnavi S, Ghoryani M, Faridhosseini F, Zare Marzouni H, Mohammadi M. Prominent Role of T Cells and Inflammasome in Bipolar Disorder. Iran J Allergy Asthma Immunol. 2026;:1-8.
