On the immunoregulatory role of statins in multiple sclerosis: the effects on Th17 cells

  • Georgios Ntolkeras
  • Chrysanthi Barba
  • Athanasios Mavropoulos
  • Georgios K. Vasileiadis
  • Efthymios Dardiotis
  • Lazaros I. Sakkas
  • Georgios Hadjigeorgiou
  • Dimitrios P. BogdanosEmail author


Statins, the cholesterol-lowering drugs, also possess immunomodulatory properties, affecting among others T cell activation and differentiation, antigen presentation, and regulatory T cell (Tregs) maintenance and differentiation. Their effects on autoagression have led investigators to assess their clinical significance in autoimmune disease, such as multiple sclerosis (MS), a chronic progressive demyelinating disease of autoimmune nature. The dysregulated immunity noted in MS features a profound shift from Tregs dominance to Th17 cell superiority. In this review, we discuss the immunobiological basis of statins, their role in autoimmunity related to MS, and the data from experimental models and human studies on their effect on Th17 cells.


Autoimmunity Demyelination Inflammation Regulation Statin 



Antigen-presenting cell


Blood–brain barrier


Cerebrospinal fluid


Expanded Disability Status Scale


Fluorescence-activated cell sorting


Forkhead box P3






Monoclonal antibodies


Myelin basic protein


Multiple sclerosis


Neuromyelitis optica


Peripheral blood


Peripheral blood mononuclear cells


Retinoid-related orphan receptor C


Relapsing-remitting MS


Secondary progressive MS


T-box expressed in T cells


Transforming growth factor




Tumor necrosis factor


T regulatory cells


Very late antigen


Compliance with ethical standards

Conflict of interest

The authors declared that they have no conflict of interest.


  1. 1.
    Chitnis T, Weiner HL. CNS inflammation and neurodegeneration. J Clin Invest. 2017;127(10):3577–87. Scholar
  2. 2.
    Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(4).
  3. 3.
    Chang MR, Rosen H, Griffin PR. RORs in autoimmune disease. Curr Top Microbiol Immunol. 2014;378:171–82. Scholar
  4. 4.
    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. Scholar
  5. 5.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–63. Scholar
  6. 6.
    Buehler U, Schulenburg K, Yurugi H, Solman M, Abankwa D, Ulges A, et al. Targeting prohibitins at the cell surface prevents Th17-mediated autoimmunity. EMBO J. 2018;37(16).
  7. 7.
    Hiltensperger M, Korn T. The interleukin (IL)-23/T helper (Th)17 axis in experimental autoimmune encephalomyelitis and multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(1).
  8. 8.
    Paroni M, Maltese V, De Simone M, Ranzani V, Larghi P, Fenoglio C, et al. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses. J Allergy Clin Immunol. 2017;140(3):797–808. Scholar
  9. 9.
    Muls N, Nasr Z, Dang HA, Sindic C, van Pesch V. IL-22, GM-CSF and IL-17 in peripheral CD4+ T cell subpopulations during multiple sclerosis relapses and remission. Impact of corticosteroid therapy. PLoS One. 2017;12(3):e0173780. Scholar
  10. 10.
    Tahmasebinia F, Pourgholaminejad A. The role of Th17 cells in auto-inflammatory neurological disorders. Prog Neuro-Psychopharmacol Biol Psychiatry. 2017;79(Pt B):408–16. Scholar
  11. 11.
    Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T. The role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediat Inflamm. 2017;2017:3908061–11. Scholar
  12. 12.
    Venken K, Hellings N, Broekmans T, Hensen K, Rummens JL, Stinissen P. Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J Immunol. 2008;180(9):6411–20.CrossRefPubMedGoogle Scholar
  13. 13.
    Mastorodemos V, Ioannou M, Verginis P. Cell-based modulation of autoimmune responses in multiple sclerosis and experimental autoimmmune encephalomyelitis: therapeutic implications. Neuroimmunomodulation. 2015;22(3):181–95. Scholar
  14. 14.
    Abdolahi M, Yavari P, Honarvar NM, Bitarafan S, Mahmoudi M, Saboor-Yaraghi AA. Molecular mechanisms of the action of vitamin a in Th17/Treg axis in multiple sclerosis. J Mol Neurosci. 2015;57(4):605–13. Scholar
  15. 15.
    Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117. Scholar
  16. 16.
    Bettini M, Vignali DA. Regulatory T cells and inhibitory cytokines in autoimmunity. Curr Opin Immunol. 2009;21(6):612–8. Scholar
  17. 17.
    Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune neuroinflammation. Immunol Rev. 2014;259(1):231–44. Scholar
  18. 18.
    Horwitz DA, Zheng SG, Gray JD. Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol. 2008;29(9):429–35. Scholar
  19. 19.
    Sakkas LI, Mavropoulos A, Perricone C, Bogdanos DP. IL-35: a new immunomodulator in autoimmune rheumatic diseases. Immunol Res. 2018;66(3):305–12. Scholar
  20. 20.
    Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, et al. ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors. Sci Signal. 2011;4(162):ra12. Scholar
  21. 21.
    Hao S, Chen X, Wang F, Shao Q, Liu J, Zhao H, et al. Breast cancer cells-derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells. Carcinogenesis. 2018;39:1488–96. Scholar
  22. 22.
    Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19(6):739–46. Scholar
  23. 23.
    Shao TY, Hsu LH, Chien CH, Chiang BL. Novel Foxp3(−) IL-10(−) regulatory T-cells induced by B-cells alleviate intestinal inflammation in vivo. Sci Rep. 2016;6:32415. Scholar
  24. 24.
    Kadowaki A, Miyake S, Saga R, Chiba A, Mochizuki H, Yamamura T. Gut environment-induced intraepithelial autoreactive CD4(+) T cells suppress central nervous system autoimmunity via LAG-3. Nat Commun. 2016;7:11639. Scholar
  25. 25.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8. Scholar
  26. 26.
    Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9(6):641–9. Scholar
  27. 27.
    Li L, Kim J, Boussiotis VA. IL-1beta-mediated signals preferentially drive conversion of regulatory T cells but not conventional T cells into IL-17-producing cells. J Immunol. 2010;185(7):4148–53. Scholar
  28. 28.
    Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008;112(6):2340–52. Scholar
  29. 29.
    Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood. 2009;113(18):4240–9. Scholar
  30. 30.
    Li L, Boussiotis VA. Molecular and functional heterogeneity of T regulatory cells. Clin Immunol. 2011;141(3):244–52. Scholar
  31. 31.
    Dombrowski Y, O'Hagan T, Dittmer M, Penalva R, Mayoral SR, Bankhead P, et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci. 2017;20(5):674–80. Scholar
  32. 32.
    Tao Y, Zhang X, Chopra M, Kim MJ, Buch KR, Kong D, et al. The role of endogenous IFN-beta in the regulation of Th17 responses in patients with relapsing-remitting multiple sclerosis. J Immunol. 2014;192(12):5610–7. Scholar
  33. 33.
    Sacramento PM, Monteiro C, Dias ASO, Kasahara TM, Ferreira TB, Hygino J, et al. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4(+) T-cell subsets in multiple sclerosis patients. Eur J Immunol. 2018;48(8):1376–88. Scholar
  34. 34.
    Lowther DE, Chong DL, Ascough S, Ettorre A, Ingram RJ, Boyton RJ, et al. Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response. Acta Neuropathol. 2013;126(4):501–15. Scholar
  35. 35.
    Alvarez-Sanchez N, Cruz-Chamorro I, Diaz-Sanchez M, Lardone PJ, Guerrero JM, Carrillo-Vico A. Peripheral CD39-expressing T regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients. Sci Rep. 2019;9(1):2302. Scholar
  36. 36.
    Toker A, Slaney CY, Backstrom BT, Harper JL. Glatiramer acetate treatment directly targets CD11b(+)Ly6G(−) monocytes and enhances the suppression of autoreactive T cells in experimental autoimmune encephalomyelitis. Scand J Immunol. 2011;74(3):235–43. Scholar
  37. 37.
    Rodi M, Dimisianos N, de Lastic AL, Sakellaraki P, Deraos G, Matsoukas J, et al. Regulatory cell populations in relapsing-remitting multiple sclerosiS (RRMS) patients: effect of disease activity and treatment regimens. Int J Mol Sci. 2016;17(9).
  38. 38.
    Pant AB, Wang Y, Mielcarz DW, Kasper EJ, Telesford KM, Mishra M, et al. Alteration of CD39+Foxp3+ CD4 T cell and cytokine levels in EAE/MS following anti-CD52 treatment. J Neuroimmunol. 2017;303:22–30. Scholar
  39. 39.
    Lee J, Park N, Park JY, Kaplan BLF, Pruett SB, Park JW, et al. Induction of immunosuppressive CD8(+)CD25(+)FOXP3(+) regulatory T cells by suboptimal stimulation with staphylococcal enterotoxin C1. J Immunol. 2018;200(2):669–80. Scholar
  40. 40.
    Sinha S, Itani FR, Karandikar NJ. Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res. 2014;59(1–3):254–65. Scholar
  41. 41.
    York NR, Mendoza JP, Ortega SB, Benagh A, Tyler AF, Firan M, et al. Immune regulatory CNS-reactive CD8+T cells in experimental autoimmune encephalomyelitis. J Autoimmun. 2010;35(1):33–44. Scholar
  42. 42.
    Deiss A, Brecht I, Haarmann A, Buttmann M. Treating multiple sclerosis with monoclonal antibodies: a 2013 update. Expert Rev Neurother. 2013;13(3):313–35. Scholar
  43. 43.
    Havrdova E, Belova A, Goloborodko A, Tisserant A, Wright A, Wallstroem E, et al. Activity of secukinumab, an anti-IL-17A antibody, on brain lesions in RRMS: results from a randomized, proof-of-concept study. J Neurol. 2016;263(7):1287–95. Scholar
  44. 44.
    Balasa RI, Simu M, Voidazan S, Barcutean LI, Bajko Z, Hutanu A, et al. Natalizumab changes the peripheral profile of the Th17 panel in MS patients: new mechanisms of action. CNS Neurol Disord Drug Targets. 2017;16(9):1018–26. Scholar
  45. 45.
    Moreno Torres I, Garcia-Merino A. Anti-CD20 monoclonal antibodies in multiple sclerosis. Expert Rev Neurother. 2017;17(4):359–71. Scholar
  46. 46.
    Mulero P, Midaglia L, Montalban X. Ocrelizumab: a new milestone in multiple sclerosis therapy. Ther Adv Neurol Disord. 2018;11:1756286418773025. Scholar
  47. 47.
    Evan JR, Bozkurt SB, Thomas NC, Bagnato F. Alemtuzumab for the treatment of multiple sclerosis. Expert Opin Biol Ther. 2018;18(3):323–34. Scholar
  48. 48.
    Zeiser R. Immune modulatory effects of statins. Immunology. 2018;154(1):69–75. Scholar
  49. 49.
    Rehfield P, Kopes-Kerr C, Clearfield M. The evolution or revolution of statin therapy in primary prevention: where do we go from here? Curr Atheroscler Rep. 2013;15(2):298. Scholar
  50. 50.
    Hashemi M, Hoshyar R, Ande SR, Chen QM, Solomon C, Zuse A, et al. Mevalonate cascade and its regulation in cholesterol metabolism in different tissues in health and disease. Curr Mol Pharmacol. 2017;10(1):13–26. Scholar
  51. 51.
    Kagami S, Owada T, Kanari H, Saito Y, Suto A, Ikeda K, et al. Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells. Int Immunol. 2009;21(6):679–89. Scholar
  52. 52.
    Steffens S, Mach F. Anti-inflammatory properties of statins. Semin Vasc Med. 2004;4(4):417–22. Scholar
  53. 53.
    Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circ Res. 2017;120(1):229–43. Scholar
  54. 54.
    Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol. 2005;25(2):287–94. Scholar
  55. 55.
    Meroni PL, Luzzana C, Ventura D. Anti-inflammatory and immunomodulating properties of statins. An additional tool for the therapeutic approach of systemic autoimmune diseases? Clin Rev Allergy Immunol. 2002;23(3):263–77. Scholar
  56. 56.
    Khattri S, Zandman-Goddard G. Statins and autoimmunity. Immunol Res. 2013;56(2–3):348–57. Scholar
  57. 57.
    Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995;333(10):621–7. Scholar
  58. 58.
    Pazik J, Ostrowska J, Lewandowski Z, Mroz A, Perkowska-Ptasinska A, Baczkowska T, et al. Renin-angiotensin-aldosterone system inhibitors and statins prolong graft survival in post-transplant glomerulonephritis. Ann Transplant. 2008;13(4):41–5.PubMedGoogle Scholar
  59. 59.
    Liu WH, Xu XH, Luo Q, Zhang HL, Wang Y, Xi QY, et al. Inhibition of the rhoA/rho-associated, coiled-coil-containing protein kinase-1 pathway is involved in the therapeutic effects of simvastatin on pulmonary arterial hypertension. Clin Exp Hypertens. 2018;40(3):224–30. Scholar
  60. 60.
    Ulivieri C, Baldari CT. Statins: from cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol Res. 2014;88:41–52. Scholar
  61. 61.
    Zeiser R, Maas K, Youssef S, Durr C, Steinman L, Negrin RS. Regulation of different inflammatory diseases by impacting the mevalonate pathway. Immunology. 2009;127(1):18–25. Scholar
  62. 62.
    Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–30. Scholar
  63. 63.
    Muller AL, Freed DH. Basic and clinical observations of mevalonate depletion on the mevalonate signaling pathway. Curr Mol Pharmacol. 2017;10(1):6–12. Scholar
  64. 64.
    Tricarico PM, Crovella S, Celsi F. Mevalonate pathway blockade, mitochondrial dysfunction and autophagy: a possible link. Int J Mol Sci. 2015;16(7):16067–84. Scholar
  65. 65.
    Park SY, Lee JS, Ko YJ, Kim AR, Choi MK, Kwak MK, et al. Inhibitory effect of simvastatin on the TNF-alpha- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation. Arch Pharm Res. 2008;31(2):195–204.CrossRefPubMedGoogle Scholar
  66. 66.
    Zhang X, Tao Y, Wang J, Garcia-Mata R, Markovic-Plese S. Simvastatin inhibits secretion of Th17-polarizing cytokines and antigen presentation by DCs in patients with relapsing remitting multiple sclerosis. Eur J Immunol. 2013;43(1):281–9. Scholar
  67. 67.
    Forero-Pena DA, Gutierrez FR. Statins as modulators of regulatory T-cell biology. Mediat Inflamm. 2013;2013:167086–10. Scholar
  68. 68.
    Chalubinski M, Broncel M. Influence of statins on effector and regulatory immune mechanisms and their potential clinical relevance in treating autoimmune disorders. Med Sci Monit. 2010;16(11):RA245–51.PubMedGoogle Scholar
  69. 69.
    Xu H, Li XL, Yue LT, Li H, Zhang M, Wang S, et al. Therapeutic potential of atorvastatin-modified dendritic cells in experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up-regulated T regulatory cells and NKR-P1(+) cells. J Neuroimmunol. 2014;269(1–2):28–37. Scholar
  70. 70.
    Reuter B, Rodemer C, Grudzenski S, Meairs S, Bugert P, Hennerici MG, et al. Effect of simvastatin on MMPs and TIMPs in human brain endothelial cells and experimental stroke. Transl Stroke Res. 2015;6(2):156–9. Scholar
  71. 71.
    Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, Hartung HP, et al. Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology. 2002;59(7):990–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Luan Z, Chase AJ, Newby AC. Statins inhibit secretion of metalloproteinases-1, -2, -3, and -9 from vascular smooth muscle cells and macrophages. Arterioscler Thromb Vasc Biol. 2003;23(5):769–75. Scholar
  73. 73.
    Cerda A, Rodrigues AC, Alves C, Genvigir FD, Fajardo CM, Dorea EL, et al. Modulation of adhesion molecules by cholesterol-lowering therapy in mononuclear cells from hypercholesterolemic patients. Cardiovasc Ther. 2015;33(4):168–76. Scholar
  74. 74.
    Shimabukuro-Vornhagen A, Zoghi S, Liebig TM, Wennhold K, Chemitz J, Draube A, et al. Inhibition of protein geranylgeranylation specifically interferes with CD40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity. J Immunol. 2014;193(10):5294–305. Scholar
  75. 75.
    Alber HF, Frick M, Suessenbacher A, Doerler J, Schirmer M, Stocker EM, et al. Effect of atorvastatin on circulating proinflammatory T-lymphocyte subsets and soluble CD40 ligand in patients with stable coronary artery disease--a randomized, placebo-controlled study. Am Heart J. 2006;151(1):139–139.e7. Scholar
  76. 76.
    Kubatka P, Kruzliak P, Rotrekl V, Jelinkova S, Mladosievicova B. Statins in oncological research: from experimental studies to clinical practice. Crit Rev Oncol Hematol. 2014;92(3):296–311. Scholar
  77. 77.
    Gauthaman K, Fong CY, Bongso A. Statins, stem cells, and cancer. J Cell Biochem. 2009;106(6):975–83. Scholar
  78. 78.
    Link A, Selejan S, Hewera L, Walter F, Nickenig G, Bohm M. Rosuvastatin induces apoptosis in CD4(+)CD28 (null) T cells in patients with acute coronary syndromes. Clin Res Cardiol. 2011;100(2):147–58. Scholar
  79. 79.
    Brinkkoetter PT, Gottmann U, Schulte J, van der Woude FJ, Braun C, Yard BA. Atorvastatin interferes with activation of human CD4(+) T cells via inhibition of small guanosine triphosphatase (GTPase) activity and caspase-independent apoptosis. Clin Exp Immunol. 2006;146(3):524–32. Scholar
  80. 80.
    Samson KT, Minoguchi K, Tanaka A, Oda N, Yokoe T, Okada S, et al. Effect of fluvastatin on apoptosis in human CD4+ T cells. Cell Immunol. 2005;235(2):136–44. Scholar
  81. 81.
    Cafforio P, Dammacco F, Gernone A, Silvestris F. Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis. 2005;26(5):883–91. Scholar
  82. 82.
    Yilmaz A, Reiss C, Tantawi O, Weng A, Stumpf C, Raaz D, et al. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis. 2004;172(1):85–93.CrossRefPubMedGoogle Scholar
  83. 83.
    Ghittoni R, Napolitani G, Benati D, Ulivieri C, Patrussi L, Laghi Pasini F, et al. Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol. 2006;36(11):2885–93. Scholar
  84. 84.
    Zhang X, Markovic-Plese S. Statins’ immunomodulatory potential against Th17 cell-mediated autoimmune response. Immunol Res. 2008;41(3):165–74. Scholar
  85. 85.
    Ulivieri C, Fanigliulo D, Benati D, Pasini FL, Baldari CT. Simvastatin impairs humoral and cell-mediated immunity in mice by inhibiting lymphocyte homing, T-cell activation and antigen cross-presentation. Eur J Immunol. 2008;38(10):2832–44. Scholar
  86. 86.
    Lee CS, Shin YJ, Won C, Lee YS, Park CG, Ye SK, et al. Simvastatin acts as an inhibitor of interferon gamma-induced cycloxygenase-2 expression in human THP-1 cells, but not in murine RAW264.7 cells. Biocell. 2009;33(2):107–14.PubMedGoogle Scholar
  87. 87.
    Maneechotesuwan K, Kasetsinsombat K, Wamanuttajinda V, Wongkajornsilp A, Barnes PJ. Statins enhance the effects of corticosteroids on the balance between regulatory T cells and Th17 cells. Clin Exp Allergy. 2013;43(2):212–22. Scholar
  88. 88.
    Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S. Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008;180(10):6988–96.CrossRefPubMedGoogle Scholar
  89. 89.
    Wang Y, Li D, Jones D, Bassett R, Sale GE, Khalili J, et al. Blocking LFA-1 activation with lovastatin prevents graft-versus-host disease in mouse bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15(12):1513–22. Scholar
  90. 90.
    Godoy JC, Niesman IR, Busija AR, Kassan A, Schilling JM, Schwarz A, et al. Atorvastatin, but not pravastatin, inhibits cardiac Akt/mTOR signaling and disturbs mitochondrial ultrastructure in cardiac myocytes. FASEB J. 2018:fj201800876R.
  91. 91.
    Tang TT, Song Y, Ding YJ, Liao YH, Yu X, Du R, et al. Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis. J Lipid Res. 2011;52(5):1023–32. Scholar
  92. 92.
    Cheng SM, Lai JH, Yang SP, Tsao TP, Ho LJ, Liou JT, et al. Modulation of human T cells signaling transduction by lovastatin. Int J Cardiol. 2010;140(1):24–33. Scholar
  93. 93.
    Leuenberger T, Pfueller CF, Luessi F, Bendix I, Paterka M, Prozorovski T, et al. Modulation of dendritic cell immunobiology via inhibition of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. PLoS One. 2014;9(7):e100871. Scholar
  94. 94.
    Li XL, Dou YC, Liu Y, Shi CW, Cao LL, Zhang XQ, et al. Atorvastatin ameliorates experimental autoimmune neuritis by decreased Th1/Th17 cytokines and up-regulated T regulatory cells. Cell Immunol. 2011;271(2):455–61. Scholar
  95. 95.
    Meng X, Zhang K, Li J, Dong M, Yang J, An G, et al. Statins induce the accumulation of regulatory T cells in atherosclerotic plaque. Mol Med. 2012;18:598–605. Scholar
  96. 96.
    Mausner-Fainberg K, Luboshits G, Mor A, Maysel-Auslender S, Rubinstein A, Keren G, et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis. 2008;197(2):829–39. Scholar
  97. 97.
    Tintore M, Vidal-Jordana A, Sastre-Garriga J. Treatment of multiple sclerosis - success from bench to bedside. Nat Rev Neurol. 2018;15:53–8. Scholar
  98. 98.
    Zettl UK, Hecker M, Aktas O, Wagner T, Rommer PS. Interferon beta-1a and beta-1b for patients with multiple sclerosis: updates to current knowledge. Expert Rev Clin Immunol. 2018;14(2):137–53. Scholar
  99. 99.
    Montes Diaz G, Hupperts R, Fraussen J, Somers V. Dimethyl fumarate treatment in multiple sclerosis: recent advances in clinical and immunological studies. Autoimmun Rev. 2018;17:1240–50. Scholar
  100. 100.
    Dargahi N, Katsara M, Tselios T, Androutsou ME, de Courten M, Matsoukas J, et al. Multiple sclerosis: immunopathology and treatment update. Brain Sci. 2017;7(7).
  101. 101.
    Ciurleo R, Bramanti P, Marino S. Role of statins in the treatment of multiple sclerosis. Pharmacol Res. 2014;87:133–43. Scholar
  102. 102.
    Stanislaus R, Singh AK, Singh I. Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis. J Neurosci Res. 2001;66(2):155–62. Scholar
  103. 103.
    Stanislaus R, Pahan K, Singh AK, Singh I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. Neurosci Lett. 1999;269(2):71–4.CrossRefPubMedGoogle Scholar
  104. 104.
    Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest. 1997;100(11):2671–9. Scholar
  105. 105.
    Greenwood J, Walters CE, Pryce G, Kanuga N, Beraud E, Baker D, et al. Lovastatin inhibits brain endothelial cell rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis. FASEB J. 2003;17(8):905–7. Scholar
  106. 106.
    Bhardwaj S, Coleman CI, Sobieraj DM. Efficacy of statins in combination with interferon therapy in multiple sclerosis: a meta-analysis. Am J Health Syst Pharm. 2012;69(17):1494–9. Scholar
  107. 107.
    Chen Z, Yang D, Peng X, Lin J, Su Z, Li J, et al. Beneficial effect of atorvastatin-modified dendritic cells pulsed with myelin oligodendrocyte glycoprotein autoantigen on experimental autoimmune encephalomyelitis. Neuroreport. 2018;29(4):317–27. Scholar
  108. 108.
    de Oliveira DM, de Oliveira EM, Ferrari Mde F, Semedo P, Hiyane MI, Cenedeze MA, et al. Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration. Inflammopharmacology. 2015;23(6):343–54. Scholar
  109. 109.
    Abtahi Froushani SM, Delirezh N, Hobbenaghi R, Mosayebi G. Synergistic effects of atorvastatin and all-trans retinoic acid in ameliorating animal model of multiple sclerosis. Immunol Investig. 2014;43(1):54–68. Scholar
  110. 110.
    Weber MS, Prod'homme T, Youssef S, Dunn SE, Steinman L, Zamvil SS. Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation. 2014;11:29. Scholar
  111. 111.
    Li Z, Chen L, Niu X, Liu J, Ping M, Li R, et al. Immunomodulatory synergy by combining atorvastatin and rapamycin in the treatment of experimental autoimmune encephalomyelitis (EAE). J Neuroimmunol. 2012;250(1–2):9–17. Scholar
  112. 112.
    Paintlia AS, Paintlia MK, Singh I, Singh AK. Combined medication of lovastatin with rolipram suppresses severity of experimental autoimmune encephalomyelitis. Exp Neurol. 2008;214(2):168–80. Scholar
  113. 113.
    Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol. 2007;8(2):172–80. Scholar
  114. 114.
    Nath N, Giri S, Prasad R, Singh AK, Singh I. Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol. 2004;172(2):1273–86.CrossRefPubMedGoogle Scholar
  115. 115.
    Paintlia AS, Paintlia MK, Singh AK, Stanislaus R, Gilg AG, Barbosa E, et al. Regulation of gene expression associated with acute experimental autoimmune encephalomyelitis by lovastatin. J Neurosci Res. 2004;77(1):63–81. Scholar
  116. 116.
    Paintlia AS, Paintlia MK, Hollis BW, Singh AK, Singh I. Interference with RhoA-ROCK signaling mechanism in autoreactive CD4+ T cells enhances the bioavailability of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis. Am J Pathol. 2012;181(3):993–1006. Scholar
  117. 117.
    Paintlia AS, Paintlia MK, Singh AK, Singh I. Modulation of rho-rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-alpha-dependent mechanism. Glia. 2013;61(9):1500–17. Scholar
  118. 118.
    Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420(6911):78–84. Scholar
  119. 119.
    Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T, et al. Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin. J Exp Med. 2003;197(6):725–33. Scholar
  120. 120.
    Paintlia AS, Paintlia MK, Singh I, Singh AK. Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis. Am J Pathol. 2006;169(3):1012–25.CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Stuve O, Youssef S, Weber MS, Nessler S, von Budingen HC, Hemmer B, et al. Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Invest. 2006;116(4):1037–44. Scholar
  122. 122.
    Pihl-Jensen G, Tsakiri A, Frederiksen JL. Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs. 2015;29(4):277–91. Scholar
  123. 123.
    Togha M, Karvigh SA, Nabavi M, Moghadam NB, Harirchian MH, Sahraian MA, et al. Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler. 2010;16(7):848–54. Scholar
  124. 124.
    Lanzillo R, Quarantelli M, Pozzilli C, Trojano M, Amato MP, Marrosu MG, et al. No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon beta1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study). Mult Scler. 2016;22(9):1163–73. Scholar
  125. 125.
    Lanzillo R, Orefice G, Quarantelli M, Rinaldi C, Prinster A, Ventrella G, et al. Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler. 2010;16(4):450–4. Scholar
  126. 126.
    Ghasami K, Faraji F, Fazeli M, Ghazavi A, Mosayebi G. Interferon beta-1a and atorvastatin in the treatment of multiple sclerosis. Iran J Immunol. 2016;13(1):16–26.PubMedGoogle Scholar
  127. 127.
    Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383(9936):2213–21. Scholar
  128. 128.
    Zhang X, Tao Y, Troiani L, Markovic-Plese S. Simvastatin inhibits IFN regulatory factor 4 expression and Th17 cell differentiation in CD4+ T cells derived from patients with multiple sclerosis. J Immunol. 2011;187(6):3431–7. Scholar
  129. 129.
    Vollmer T, Key L, Durkalski V, Tyor W, Corboy J, Markovic-Plese S, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet. 2004;363(9421):1607–8. Scholar
  130. 130.
    Chan D, Binks S, Nicholas JM, Frost C, Cardoso MJ, Ourselin S, et al. Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial. Lancet Neurol. 2017;16(8):591–600. Scholar
  131. 131.
    Paul F, Waiczies S, Wuerfel J, Bellmann-Strobl J, Dorr J, Waiczies H, et al. Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis. PLoS One. 2008;3(4):e1928. Scholar
  132. 132.
    Li XL, Zhang ZC, Zhang B, Jiang H, Yu CM, Zhang WJ, et al. Atorvastatin calcium in combination with methylprednisolone for the treatment of multiple sclerosis relapse. Int Immunopharmacol. 2014;23(2):546–9. Scholar
  133. 133.
    Kamm CP, Mattle HP, Group SS. Swiss atorvastatin and interferon Beta-1b trial in multiple sclerosis (SWABIMS)--rationale, design and methodology. Trials. 2009;10:115. Scholar
  134. 134.
    Kamm CP, El-Koussy M, Humpert S, Findling O, Burren Y, Schwegler G, et al. Atorvastatin added to interferon beta for relapsing multiple sclerosis: 12-month treatment extension of the randomized multicenter SWABIMS trial. PLoS One. 2014;9(1):e86663. Scholar
  135. 135.
    Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology. 2008;71(18):1390–5. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Georgios Ntolkeras
    • 1
  • Chrysanthi Barba
    • 1
  • Athanasios Mavropoulos
    • 1
  • Georgios K. Vasileiadis
    • 1
  • Efthymios Dardiotis
    • 2
  • Lazaros I. Sakkas
    • 1
  • Georgios Hadjigeorgiou
    • 2
    • 3
  • Dimitrios P. Bogdanos
    • 1
    Email author
  1. 1.Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health SciencesUniversity General Hospital of Larissa, University of ThessalyLarissaGreece
  2. 2.Department of Neurology and Laboratory of Neurogenetics, Faculty of Medicine, School of Health SciencesUniversity General Hospital of Larissa, University of ThessalyLarissaGreece
  3. 3.Department of NeurologyUniversity of Cyprus Medical SchoolNicosiaCyprus

Personalised recommendations