Simvastatin alleviates experimental autoimmune encephalomyelitis through regulating the balance of Th17 and Treg in mice
Main Article Content
Keywords
Experimental Autoimmune Encephalomyelitis, Multiple Sclerosis, Simvastatin, Th17, Treg
Abstract
The aim of this study was to elucidate the therapeutic effect of simvastatin on experimental autoimmune encephalomyelitis (EAE) by regulating the balance between Th17 and Treg cells in mice. C57BL/6 mice were randomly divided into four groups: normal group, EAE group, simvastatin (2 and 10 mg/kg) group, and AG490 group (with AG490 serving as the positive control). Neurological function scores of mice were assessed daily. The four groups received treatments of normal saline, normal saline, and simvastatin (2 and 10 mg/kg), respectively. In the AG490 group, mice were injected intraperitoneally with AG490 (1 mg) every other day, and treatment was halted after 3 weeks. The spinal cord was stained with hematoxylin and eosin (H&E), and immunohistochemical staining for retinoic acid receptor-related orphan receptor γ(RORγ) and Foxp3 (Foxp3) was performed. Spleen samples were taken for Th17 and Treg analysis using flow cytometry. The levels of interleukin-17 and transforming growth factor-β (TGF-β) were detected using enzyme-linked immunosorbent assay (ELISA). In the simvastatin and AG490 groups, recovery from neurological impairment was earlier compared to the EAE group, and the symptoms were notably improved. Both simvastatin and AG490 reduced focal inflammation, decreased RORγ-positive cell infiltration, and significantly increased the number of FOXP3-positive cells. The number of Th17 cells and the level of IL-17 in the spleen were decreased in the simvastatin and AG490 treatment groups, while the number of Treg cells and TGF-β levels were significantly increased across all treatment groups. Simvastatin exhibits anti-inflammatory and immunomodulatory effects, potentially alleviating symptoms of neurological dysfunction of EAE. Regulating the balance between Th17 and Treg may represent a therapeutic mechanism for simvastatin in treating EAE.
References
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30. Venkatesha SH, Dudics S, Weingartner E, et al. Altered Th17/Treg balance and dysregulated IL-1b response influence susceptibility/resistance to experimental autoimmune arthritis. Int J Immunopathol Pharmacol. 2015;28(3):318-328. 10.1177/0394632015595757
31. Ghadiri M, Rezk A, Li R, et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e340. 10.1212/NXI.0000000000000340
32. Dargahi N, Katsara M, Tselios T, et al. Multiple sclerosis: immunopathology and treatment update. Brain Sci. 2017; 7(7):78. 10.3390/brainsci7070078
33. Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. 10.1186/s12974-017-0892-8
34. Venkatesha H, Dudics S, Weingartner E, et al. Altered Th17/Treg balance and dysregulated IL-1β response influence susceptibility/resistance to experimental autoimmune arthritis. Int J Immunopathol Pharmacol. 2015;28(3):318-328. 10.1177/0394632015595757
35. Lu PX, Cao YP, M Wang MH, et al. Mature dendritic cells cause Th17/Treg imbalance by secreting TGF-β1 and IL-6 in the pathogenesis of experimental autoimmune encephalomyelitis. Cent Eur J Immunol. 2016;41(2):143-152. 10.5114/ceji.2016.60987
36. Segal BM. The diversity of encephalitogenic CD4+ t cells in multiple sclerosis and its animal models. J Clin Med. 2019;8(1):120. 10.3390/jcm8010120
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39. Zhao Q, Cheng WJ, I Xi YB, et al. FN-beta regulates Th17 differentiation partly through the inhibition of osteopontin in experimental autoimmune encephalomyelitis. Mol Immunol. 2018;93:20-30. 10.1016/j.molimm.2017.11.002
40. Teixeira NB, Sant’Anna MB, Giardini AC, et al. Crotoxin down-modulates proinflammatory cells and alleviates pain on the MOG35-55-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Brain Behav Immun. 2020;84:253-268. 10.1016/j.bbi.2019.12.009
41. Cerboni S, Gehrmann U, Preite S, et al. Cytokine-regulated Th17 plasticity in human health and diseases. Immunology. 2021;163(1):3-18. 10.1111/imm.13280
2. Hosseini A, Masjedi A, Baradaran B, et al. Dimethyl fumarate: regulatory effects on the immune system in the treatment of multiple sclerosis. J Cell Physiol. 2019;234(7):9943-9955. 10.1002/jcp.27930
3. Wunsch M, Jabari S, Voussen B, et al. The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol. 2017;134(2):281-295. 10.1007/s00401-017-1742-6
4. Hosseinzadeh A, Baneshi MR, Sedighi B, et al. Incidence of multiple sclerosis in Iran: a nationwide, population-based study. Public Health. 2019;175:138-144. 10.1016/j.puhe.2019.07.013
5. Spear ET, Holt EA, Joyce EJ, et al. Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil. 2018;30(9):e13349. 10.1111/nmo.13349
6. Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018;97(4):742-768. 10.1016/j.neuron.2018.01.021
7. TaSKapilioGLu ÖZ. Recent advances in the treatment for multiple sclerosis; current new drugs specific for multiple sclerosis. Noro Psikiyatr Ars. 2018;55(Suppl1):S15-S20. 10.29399/npa.23402
8. Stockinger B, Omenetti S. The dichotomous nature of T Helper 17 cells. Nat Rev Immunol. 2017;17(9):535-544. 10.1038/nri.2017.50
9. Omenetti S, Bussi C, Metidji A, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity. 2019;51(1):77-89.e6. 10.1016/j.immuni.2019.05.004
10. Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. 2019;41(3):283-297. 10.1007/s00281-019-00733-8
11. Balasa R, Barcutean L, Balasa A, et al. The action of TH17 cells on blood-brain barrier in multiple sclerosis and experimental autoimmune encephalomyelitis. Hum Immunol. 2020;81(5):237-243. 10.1016/j.humimm.2020.02.009
12. Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(4):a029025. 10.1101/cshperspect.a029025
13. Stadhouders R, Lubberts E, Hendriks RW. A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. J Autoimmun. 2018;87:1-15. 10.1016/j.jaut.2017.12.007
14. Yang SJ, Xie CC, Chen Y, et al. Differential roles of TNFalpha-TNFR1 and TNFalpha-TNFR2 in the differentiation and function of CD4(+)Foxp3(+) induced Treg cells in vitro and in vivo periphery in autoimmune diseases. Cell Death Dis. 2019;10(1):27. 10.1038/s41419-018-1266-6
15. Rodrigues KA, Rocha RT, Mulinari FF, et al. Exploring the Brazilian diversity of aspergillus sp. strains for lovastatin and itaconic acid production. Fungal Genet Biol. 2020;138:103367. 10.1016/j.fgb.2020.103367
16. Loera-Valencia R, Goikolea J, Parrado-Fernandez C, et al. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: potential novel targets for treatment. J Steroid Biochem Mol Biol. 2019;190:104-114. 10.1016/j.jsbmb.2019.03.003
17. Hasan H, Rahim MHA, Campbell L, et al. Overexpression of acetyl-CoA carboxylase in Aspergillus terreus to increase lovastatin production. N Biotechnol. 2018;44:64-71. 10.1016/j.nbt.2018.04.008
18. Yoon LS, Goodman MT, Rimel BJ, et al. Statin use and survival in elderly patients with endometrial cancer. Gynecol Oncol. 2015;137(2):252-257. 10.1016/j.ygyno.2015.01.549
19. Schneider C, Schuetz G, Zollner TM. Acute neuroinflammation in lewis rats—a model for acute multiple sclerosis relapses. J Neuroimmunol. 2009;213(1-2):84-90. 10.1016/j.jneuroim.2009.05.015
20. Robichon K, Patel V, Connor B, et al. Clozapine reduces infiltration into the CNS by targeting migration in experimental autoimmune encephalomyelitis. J Neuroinflammation. 2020;17(1):53. 10.1016/j.jneuroim.2009.05.015
21. Côté-Daigneault J, Mehandru S, Ungaro R, et al. Potential immunomodulatory effects of statins in in flammatory bowel disease. Inflamm Bowel Dis. 2016;22(3):724-732. 10.1097/MIB.0000000000000640
22. Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607-1608. 10.1016/S0140-6736(04)16205-3
23. Haines CJ, Chen Y, Blumenschein WM, et al. Autoimmune memory T helper 17 cell function and expansion are dependent on interleukin-23. Cell Rep. 2013;3(5):1378-1388. 10.1016/j.celrep.2013.03.035
24. Kohm AP, Carpentier PA, Anger HA, et al. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol. 2002;169(9):4712-4716. 10.4049/jimmunol.169.9.4712
25. Haghmorad D, Mahmoudi MB, Salehipour Z, et al. Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis. J Neuroimmunol. 2017;302:23-33. 10.1016/j.jneuroim.2016.11.009
26. Bettelli E, Das MP, Howard ED, et al. IL-10 is critical in regulating autoimmune encephalomyelitis, as demonstrated by studies of IL-10-and IL-4-deficient and transgenic mice. J Immunol. 1998;161(7):3299–3306. 10.4049/jimmunol.161.7.3299
27. Speck S, Lim J, Shelake S, et al. TGF-beta signaling initiated in dendritic cells instructs suppressive effects on Th17 differentiation at the site of neuroinflammation. PLoS One. 2014;9(7):e102390. 10.1371/journal.pone.0102390
28. Zhang XM, Koldzic DN, Izikson L, et al. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+ CD4+ regulatory T cells. Int Immunol. 2004;16(2):249-256. 10.1093/intimm/dxh029
29. Wu DW, Wang JT, Zhang M, et al. Altered Th17/Treg ratio in nasal polyps with distinct cytokine profile: association with patterns of inflammation and mucosal remodeling. Medicine. 2016;95(10):e2998. 10.1097/MD.0000000000002998
30. Venkatesha SH, Dudics S, Weingartner E, et al. Altered Th17/Treg balance and dysregulated IL-1b response influence susceptibility/resistance to experimental autoimmune arthritis. Int J Immunopathol Pharmacol. 2015;28(3):318-328. 10.1177/0394632015595757
31. Ghadiri M, Rezk A, Li R, et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(3):e340. 10.1212/NXI.0000000000000340
32. Dargahi N, Katsara M, Tselios T, et al. Multiple sclerosis: immunopathology and treatment update. Brain Sci. 2017; 7(7):78. 10.3390/brainsci7070078
33. Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. 10.1186/s12974-017-0892-8
34. Venkatesha H, Dudics S, Weingartner E, et al. Altered Th17/Treg balance and dysregulated IL-1β response influence susceptibility/resistance to experimental autoimmune arthritis. Int J Immunopathol Pharmacol. 2015;28(3):318-328. 10.1177/0394632015595757
35. Lu PX, Cao YP, M Wang MH, et al. Mature dendritic cells cause Th17/Treg imbalance by secreting TGF-β1 and IL-6 in the pathogenesis of experimental autoimmune encephalomyelitis. Cent Eur J Immunol. 2016;41(2):143-152. 10.5114/ceji.2016.60987
36. Segal BM. The diversity of encephalitogenic CD4+ t cells in multiple sclerosis and its animal models. J Clin Med. 2019;8(1):120. 10.3390/jcm8010120
37. Qu XB, Han JJ, Zhang Y, et al. MiR-384 regulates the Th17/Treg ratio during experimental autoimmune encephalomyelitis pathogenesis. Front Cell Neurosci. 2017;11:88. 10.3389/fncel.2017.00088
38. Lee PW, Severin ME, Lovett-Racke AE. TGF-β regulation of encephalitogenic and regulatory T cells in multiple sclerosis. Eur J Immunol. 2017;47(3):446-453. 10.1002/eji.201646716
39. Zhao Q, Cheng WJ, I Xi YB, et al. FN-beta regulates Th17 differentiation partly through the inhibition of osteopontin in experimental autoimmune encephalomyelitis. Mol Immunol. 2018;93:20-30. 10.1016/j.molimm.2017.11.002
40. Teixeira NB, Sant’Anna MB, Giardini AC, et al. Crotoxin down-modulates proinflammatory cells and alleviates pain on the MOG35-55-induced experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Brain Behav Immun. 2020;84:253-268. 10.1016/j.bbi.2019.12.009
41. Cerboni S, Gehrmann U, Preite S, et al. Cytokine-regulated Th17 plasticity in human health and diseases. Immunology. 2021;163(1):3-18. 10.1111/imm.13280
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Sep 1, 2024
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Xu, D., Wang, M., & Wang, L. (2024). Simvastatin alleviates experimental autoimmune encephalomyelitis through regulating the balance of Th17 and Treg in mice. Allergologia Et Immunopathologia, 52(5), 36-43. https://doi.org/10.15586/aei.v52i5.1100
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How to Cite
Xu, D., Wang, M., & Wang, L. (2024). Simvastatin alleviates experimental autoimmune encephalomyelitis through regulating the balance of Th17 and Treg in mice. Allergologia Et Immunopathologia, 52(5), 36-43. https://doi.org/10.15586/aei.v52i5.1100