Impact of Vitamin D and Curcumin on CD4+ and CD8+ T cells Expressing CXCR3, CCR4, and CCR6 Chemokine Receptors in Patients with Relapsing-remitting Multiple Sclerosis
-
Omid Sadatpour
,
Amirreza Azimi
,
Zahra Salehi
,
Mohammad Javad Tavassolifar
,
Ali Akbar Saboor-Yaraghi
,
Maryam Izad
Abstract
Chemokines and their receptors play a central role in mediating the migration of pathogenic T cells into the central nervous system of patients with multiple sclerosis (MS). Vitamin D and curcumin are known to possess anti-inflammatory and immunomodulatory properties; however, their combined effects on T-cell chemokine receptor expression in MS remain poorly defined.
In this study, we investigated the in vitro effects of vitamin D, curcumin, and their combination on CD4+ and CD8+ T cells expressing CXCR3, CCR6, and CCR4 in patients with relapsing-remitting MS (RRMS). Peripheral blood mononuclear cells were collected from patients in relapse (n=10), remission (n=14), and healthy controls (n=15) and analyzed using flow cytometry.
Relapse patients exhibited elevated frequencies of CXCR3+CD4+ T cells compared to healthy controls, which normalized following treatment. Increased CCR6+CD4+ T cells and CXCR3+CD8+ T cells were also observed in patients, with a significant reduction achieved only after combined treatment with vitamin D and curcumin. The combined treatment further decreased the mean fluorescence intensity of CXCR3 and CCR6 on T cells in relapse patients, while vitamin D alone specifically reduced CCR4+CCR6+CD4+ T cells, a TH17-like subset enriched during relapse.
These findings indicate that vitamin D and curcumin, particularly in combination, modulate T-cell activity by downregulating chemokine receptor expression and may represent a promising adjunctive approach for controlling immune cell migration in MS.
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24. Gosselin A, Monteiro P, Chomont N, Diaz-Griffero F, Said EA, Fonseca S, et al. Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection. J Immunol. 2010;184(3):1604-16.
25. Rolf L, Smolders J, van den Ouweland J, Hupperts R, Damoiseaux J. Correlation of different cellular assays to analyze T cell-related cytokine profiles in vitamin D3-supplemented patients with multiple sclerosis. Mol Immunol. 2019;105:198-204.
26. Kaskow BJ, Baecher-Allan C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018;8(4).
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28. Cui LY, Chu SF, Chen NH. The role of chemokines and chemokine receptors in multiple sclerosis. Int Immunopharmacol. 2020;83:106314.
29. Košćak Lukač J, Baronica KB, Šućur A, Sremec J, Tomasović S, Baronica R, et al. Serum Concentrations of Chemokines CCL20, CXCL8 and CXCL10 in Relapsing-Remitting Multiple Sclerosis and Their Association with Presence of Antibodies against Epstein-Barr Virus. Int J Mol Sci. 2024;25(15).
30. Ghafouri-Fard S, Honarmand K, Taheri M. A comprehensive review on the role of chemokines in the pathogenesis of multiple sclerosis. Metab Brain Dis. 2021;36(3):375-406.
31. Wadwa M, Klopfleisch R, Adamczyk A, Frede A, Pastille E, Mahnke K, et al. IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites. Mucosal Immunol. 2016;9(5):1263-77.
32. Finkelsztejn A. Multiple sclerosis: overview of disease-modifying agents. Perspect Medicin Chem. 2014;6:65-72.
33. Nakajima H, Fukuda K, Doi Y, Sugino M, Kimura F, Hanafusa T, et al. Expression of TH1/TH2-related chemokine receptors on peripheral T cells and correlation with clinical disease activity in patients with multiple sclerosis. Eur Neurol. 2004;52(3):162-8.
34. Sellebjerg F, Kristiansen TB, Wittenhagen P, Garred P, Eugen-Olsen J, Frederiksen JL, et al. Chemokine receptor CCR5 in interferon-treated multiple sclerosis. Acta Neurol Scand. 2007;115(6):413-8.
35. Chang JH, Cha HR, Lee DS, Seo KY, Kweon MN. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS One. 2010;5(9):e12925.
36. Zhao G, Liu Y, Yi X, Wang Y, Qiao S, Li Z, et al. Curcumin inhibiting Th17 cell differentiation by regulating the metabotropic glutamate receptor-4 expression on dendritic cells. Int Immunopharmacol. 2017;46:80-6.
2. Ward M, Goldman MD. Epidemiology and Pathophysiology of Multiple Sclerosis. Continuum (Minneap Minn). 2022;28(4):988-1005.
3. Liu R, Du S, Zhao L, Jain S, Sahay K, Rizvanov A, et al. Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target. Front Immunol. 2022;13:996469.
4. Moser T, Akgün K, Proschmann U, Sellner J, Ziemssen T. The role of TH17 cells in multiple sclerosis: Therapeutic implications. Autoimmun Rev. 2020;19(10):102647.
5. Metaxakis A, Petratou D, Tavernarakis N. Molecular Interventions towards Multiple Sclerosis Treatment. Brain Sci. 2020;10(5).
6. Tomioka R, Matsui M. Biomarkers for multiple sclerosis. Intern Med. 2014;53(5):361-5.
7. Cheng W, Chen G. Chemokines and chemokine receptors in multiple sclerosis. Mediators Inflamm. 2014;2014:659206.
8. Mony JT, Khorooshi R, Owens T. Chemokine receptor expression by inflammatory T cells in EAE. Front Cell Neurosci. 2014;8:187.
9. Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev. 2021;20(7):102846.
10. Sadeghian-Rizi T, Khanahmad H, Jahanian-Najafabadi A. Therapeutic targeting of chemokines and chemokine receptors in multiple sclerosis: opportunities and challenges. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2018;17(7):496-508.
11. da Costa DS, Hygino J, Ferreira TB, Kasahara TM, Barros PO, Monteiro C, et al. Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients. Journal of neuroimmunology. 2016;299:8-18.
12. Jafarzadeh A, Azizi SV, Arabi Z, Ahangar-Parvin R, Mohammadi-Kordkhayli M, Larussa T, et al. Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis. Nutr Neurosci. 2018:1-13.
13. Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2018;9:Cd008422.
14. Karkeni E, Marcotorchino J, Tourniaire F, Astier J, Peiretti F, Darmon P, et al. Vitamin D limits chemokine expression in adipocytes and macrophage migration in vitro and in male mice. Endocrinology. 2015;156(5):1782-93.
15. Abdul-Rahman T, Awuah WA, Mikhailova T, Kalmanovich J, Mehta A, Ng JC, et al. Antioxidant, anti-inflammatory and epigenetic potential of curcumin in Alzheimer's disease. Biofactors. 2024;50(4):693-708.
16. Jabczyk M, Nowak J, Hudzik B, Zubelewicz-Szkodzińska B. Curcumin in Metabolic Health and Disease. Nutrients. 2021;13(12).
17. Yu H, Ma L, Jiang J, Sun S. Protective effect of curcumin on neural myelin sheaths by attenuating interactions between the endoplasmic reticulum and mitochondria after compressed spinal cord. J Spine. 2016;5(4):1-6.
18. Abbott NJ. Astrocyte–endothelial interactions and blood–brain barrier permeability. Journal of anatomy. 2002;200(6):629-38.
19. Seyedzadeh MH, Safari Z, Zare A, Navashenaq JG, Kardar GA, Khorramizadeh MR. Study of curcumin immunomodulatory effects on reactive astrocyte cell function. International immunopharmacology. 2014;22(1):230-5.
20. Tegenge MA, Rajbhandari L, Shrestha S, Mithal A, Hosmane S, Venkatesan A. Curcumin protects axons from degeneration in the setting of local neuroinflammation. Experimental neurology. 2014;253:102-10.
21. Xu MX, Yu R, Shao LF, Zhang YX, Ge CX, Liu XM, et al. Up-regulated fractalkine (FKN) and its receptor CX3CR1 are involved in fructose-induced neuroinflammation: Suppression by curcumin. Brain Behav Immun. 2016;58:69-81.
22. Jafarzadeh A, Azizi SV, Arabi Z, Ahangar-Parvin R, Mohammadi-Kordkhayli M, Larussa T, et al. Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis. Nutr Neurosci. 2019;22(10):725-37.
23. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of neurology. 2011;69(2):292-302.
24. Gosselin A, Monteiro P, Chomont N, Diaz-Griffero F, Said EA, Fonseca S, et al. Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection. J Immunol. 2010;184(3):1604-16.
25. Rolf L, Smolders J, van den Ouweland J, Hupperts R, Damoiseaux J. Correlation of different cellular assays to analyze T cell-related cytokine profiles in vitamin D3-supplemented patients with multiple sclerosis. Mol Immunol. 2019;105:198-204.
26. Kaskow BJ, Baecher-Allan C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018;8(4).
27. Planas R, Metz I, Martin R, Sospedra M. Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions. Front Immunol. 2018;9:509.
28. Cui LY, Chu SF, Chen NH. The role of chemokines and chemokine receptors in multiple sclerosis. Int Immunopharmacol. 2020;83:106314.
29. Košćak Lukač J, Baronica KB, Šućur A, Sremec J, Tomasović S, Baronica R, et al. Serum Concentrations of Chemokines CCL20, CXCL8 and CXCL10 in Relapsing-Remitting Multiple Sclerosis and Their Association with Presence of Antibodies against Epstein-Barr Virus. Int J Mol Sci. 2024;25(15).
30. Ghafouri-Fard S, Honarmand K, Taheri M. A comprehensive review on the role of chemokines in the pathogenesis of multiple sclerosis. Metab Brain Dis. 2021;36(3):375-406.
31. Wadwa M, Klopfleisch R, Adamczyk A, Frede A, Pastille E, Mahnke K, et al. IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites. Mucosal Immunol. 2016;9(5):1263-77.
32. Finkelsztejn A. Multiple sclerosis: overview of disease-modifying agents. Perspect Medicin Chem. 2014;6:65-72.
33. Nakajima H, Fukuda K, Doi Y, Sugino M, Kimura F, Hanafusa T, et al. Expression of TH1/TH2-related chemokine receptors on peripheral T cells and correlation with clinical disease activity in patients with multiple sclerosis. Eur Neurol. 2004;52(3):162-8.
34. Sellebjerg F, Kristiansen TB, Wittenhagen P, Garred P, Eugen-Olsen J, Frederiksen JL, et al. Chemokine receptor CCR5 in interferon-treated multiple sclerosis. Acta Neurol Scand. 2007;115(6):413-8.
35. Chang JH, Cha HR, Lee DS, Seo KY, Kweon MN. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS One. 2010;5(9):e12925.
36. Zhao G, Liu Y, Yi X, Wang Y, Qiao S, Li Z, et al. Curcumin inhibiting Th17 cell differentiation by regulating the metabotropic glutamate receptor-4 expression on dendritic cells. Int Immunopharmacol. 2017;46:80-6.
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| CD4-positive T-lymphocytes Chemokine receptors Curcumin Multiple sclerosis Vitamin D | ||
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How to Cite
1.
Sadatpour O, Azimi A, Salehi Z, Tavassolifar MJ, Saboor-Yaraghi AA, Izad M. Impact of Vitamin D and Curcumin on CD4+ and CD8+ T cells Expressing CXCR3, CCR4, and CCR6 Chemokine Receptors in Patients with Relapsing-remitting Multiple Sclerosis. Iran J Allergy Asthma Immunol. 2026;:1-12.
