Skip to main content

Advertisement

Log in

Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor® strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Alt C, Laschinger M, Engelhardt B (2002) Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood–brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur J Immunol 32(8):2133–2144. doi:10.1002/1521-4141(200208)32:8<2133:AID-IMMU2133>3.0.CO;2-W

    Article  PubMed  CAS  Google Scholar 

  2. Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A (2002) In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 195(5):603–616. doi:10.1084/jem.20011629

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Baschant U, Frappart L, Rauchhaus U, Bruns L, Reichardt HM, Kamradt T, Brauer R, Tuckermann JP (2011) Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells. Proc Natl Acad Sci USA 108(48):19317–19322. doi:10.1073/pnas.1105857108

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Baschant U, Tuckermann J (2010) The role of the glucocorticoid receptor in inflammation and immunity. J Steroid Biochem Mol Biol 120(2-3):69–75. doi:10.1016/j.jsbmb.2010.03.058

    Article  PubMed  CAS  Google Scholar 

  5. Chen X, Oppenheim JJ, Winkler-Pickett RT, Ortaldo JR, Howard OM (2006) Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3(+) CD4(+) CD25(+) T regulatory cells in vivo and enhances their capacity to suppress EAE. Eur J Immunol 36(8):2139–2149. doi:10.1002/eji.200635873

    Article  PubMed  CAS  Google Scholar 

  6. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567. doi:10.1038/ni.2027

    Article  PubMed  CAS  Google Scholar 

  7. Cruz-Orengo L, Holman DW, Dorsey D, Zhou L, Zhang P, Wright M, McCandless EE, Patel JR, Luker GD, Littman DR, Russell JH, Klein RS (2011) CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J Exp Med 208(2):327–339. doi:10.1084/jem.20102010

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Curnow SJ, Wloka K, Faint JM, Amft N, Cheung CM, Savant V, Lord J, Akbar AN, Buckley CD, Murray PI, Salmon M (2004) Topical glucocorticoid therapy directly induces up-regulation of functional CXCR4 on primed T lymphocytes in the aqueous humor of patients with uveitis. J Immunol 172(11):7154–7161

    Article  PubMed  CAS  Google Scholar 

  9. D’Apuzzo M, Rolink A, Loetscher M, Hoxie JA, Clark-Lewis I, Melchers F, Baggiolini M, Moser B (1997) The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur J Immunol 27(7):1788–1793. doi:10.1002/eji.1830270729

    Article  PubMed  Google Scholar 

  10. Dos Santos AC, Roffe E, Arantes RM, Juliano L, Pesquero JL, Pesquero JB, Bader M, Teixeira MM, Carvalho-Tavares J (2008) Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J Neuroinflamm 5:49. doi:10.1186/1742-2094-5-49

    Article  Google Scholar 

  11. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12(6):568–575. doi:10.1038/ni.2031

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156(1):5–7

    PubMed  CAS  Google Scholar 

  13. Fleming KK, Bovaird JA, Mosier MC, Emerson MR, LeVine SM, Marquis JG (2005) Statistical analysis of data from studies on experimental autoimmune encephalomyelitis. J Neuroimmunol 170(1–2):71–84. doi:10.1016/j.jneuroim.2005.08.020

    Article  PubMed  CAS  Google Scholar 

  14. Fricker SP (2013) Physiology and pharmacology of plerixafor. Transfus Med Hemother 40(4):237–245. doi:10.1159/000354132

    Article  PubMed Central  PubMed  Google Scholar 

  15. Ghosh MC, Baatar D, Collins G, Carter A, Indig F, Biragyn A, Taub DD (2009) Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck. Blood 113(3):575–584. doi:10.1182/blood-2008-04-151803

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Haak S, Croxford AL, Kreymborg K, Heppner FL, Pouly S, Becher B, Waisman A (2009) IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J Clin Invest 119(1):61–69. doi:10.1172/JCI35997

    PubMed Central  PubMed  CAS  Google Scholar 

  17. Holman DW, Klein RS, Ransohoff RM (2011) The blood–brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta 1812(2):220–230. doi:10.1016/j.bbadis.2010.07.019

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Koukouritaki SB, Gravanis A, Stournaras C (1999) Tyrosine phosphorylation of focal adhesion kinase and paxillin regulates the signaling mechanism of the rapid nongenomic action of dexamethasone on actin cytoskeleton. Mol Med 5(11):731–742

    PubMed Central  PubMed  CAS  Google Scholar 

  19. Kumar A, Humphreys TD, Kremer KN, Bramati PS, Bradfield L, Edgar CE, Hedin KE (2006) CXCR4 physically associates with the T cell receptor to signal in T cells. Immunity 25(2):213–224. doi:10.1016/j.immuni.2006.06.015

    Article  PubMed  CAS  Google Scholar 

  20. Le Y, Zhu BM, Harley B, Park SY, Kobayashi T, Manis JP, Luo HR, Yoshimura A, Hennighausen L, Silberstein LE (2007) SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis. Immunity 27(5):811–823. doi:10.1016/j.immuni.2007.09.011

    Article  PubMed  CAS  Google Scholar 

  21. Lee HJ, Choi SC, Lee MH, Oh HM, Choi EY, Choi EJ, Yun KJ, Seo GS, Kim SW, Lee JG, Han WC, Park KI, Jun CD (2005) Increased expression of MIP-3alpha/CCL20 in peripheral blood mononuclear cells from patients with ulcerative colitis and its down-regulation by sulfasalazine and glucocorticoid treatment. Inflamm Bowel Dis 11(12):1070–1079. doi:10.1097/01.MIB.0000187576.26043.ac

    Article  PubMed  Google Scholar 

  22. Lyons JA, Ramsbottom MJ, Trotter JL, Cross AH (2002) Identification of the encephalitogenic epitopes of CNS proteolipid protein in BALB/c mice. J Autoimmun 19(4):195–201. doi:10.1006/jaut2002.0619

    Article  PubMed  Google Scholar 

  23. McCandless EE, Wang Q, Woerner BM, Harper JM, Klein RS (2006) CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J Immunol 177(11):8053–8064

    Article  PubMed  CAS  Google Scholar 

  24. McQualter JL, Darwiche R, Ewing C, Onuki M, Kay TW, Hamilton JA, Reid HH, Bernard CC (2001) Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J Exp Med 194(7):873–882. doi:10.1084/jem.194.7.873

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Michalowska-Wender G, Losy J, Szczucinski A, Biernacka-Lukanty J, Wender M (2006) Effect of methylprednisolone treatment on expression of sPECAM-1 and CXCL10 chemokine in serum of MS patients. Pharmacol Rep 58(6):920–923

    PubMed  CAS  Google Scholar 

  26. Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6(1):56–68. doi:10.1038/nrm1549

    Article  PubMed  CAS  Google Scholar 

  27. Muzio L, Cavasinni F, Marinaro C, Bergamaschi A, Bergami A, Porcheri C, Cerri F, Dina G, Quattrini A, Comi G, Furlan R, Martino G (2010) Cxcl10 enhances blood cells migration in the sub-ventricular zone of mice affected by experimental autoimmune encephalomyelitis. Mol Cell Neurosci 43(3):268–280. doi:10.1016/j.mcn.2009.11.008

    Article  PubMed  CAS  Google Scholar 

  28. Nagase H, Miyamasu M, Yamaguchi M, Kawasaki H, Ohta K, Yamamoto K, Morita Y, Hirai K (2000) Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils. J Allergy Clin Immunol 106(6):1132–1139. doi:10.1067/mai.2000.110923

    Article  PubMed  CAS  Google Scholar 

  29. Ogilvy S, Metcalf D, Print CG, Bath ML, Harris AW, Adams JM (1999) Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc Natl Acad Sci USA 96(26):14943–14948. doi:10.1073/pnas.96.26.14943

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Okutsu M, Ishii K, Niu KJ, Nagatomi R (2005) Cortisol-induced CXCR4 augmentation mobilizes T lymphocytes after acute physical stress. Am J Physiol Regul Integr Comp Physiol 288(3):R591–R599. doi:10.1152/ajpregu.00438.2004

    Article  PubMed  CAS  Google Scholar 

  31. Pender MP, Rist MJ (2001) Apoptosis of inflammatory cells in immune control of the nervous system: role of glia. Glia 36(2):137–144. doi:10.1002/glia.1103

    Article  PubMed  CAS  Google Scholar 

  32. Pountain GD, Keogan MT, Hazleman BL, Brown DL (1993) Effects of single dose compared with three days’ prednisolone treatment of healthy volunteers: contrasting effects on circulating lymphocyte subsets. J Clin Pathol 46(12):1089–1092. doi:10.1136/jcp.46.12.1089

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10(5):514–523. doi:10.1038/ni.1716

    Article  PubMed  CAS  Google Scholar 

  34. Reichardt HM, Kaestner KH, Tuckermann J, Kretz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, Schütz G (1998) DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93(4):531–541. doi:10.1016/S0092-8674(00)81183-6

    Article  PubMed  CAS  Google Scholar 

  35. Reichardt HM, Lühder F (2012) The ambivalent role of apoptosis in experimental autoimmune encephalomyelitis and multiple sclerosis. Curr Pharm Des 18(29):4453–4464. doi:10.2174/138161212802502224

    Article  PubMed  CAS  Google Scholar 

  36. Reichardt HM, Tuckermann JP, Göttlicher M, Vujic M, Weih F, Angel P, Herrlich P, Schütz G (2001) Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. Embo J 20(24):7168–7173. doi:10.1093/emboj/20.24.7168

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Reichardt SD, Föller M, Rexhepaj R, Pathare G, Minnich K, Tuckermann JP, Lang F, Reichardt HM (2012) Glucocorticoids enhance intestinal glucose uptake via the dimerized glucocorticoid receptor in enterocytes. Endocrinology 153(4):1783–1794. doi:10.1210/en.2011-1747

    Article  PubMed  CAS  Google Scholar 

  38. Schaller MD (2010) Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 123(Pt 7):1007–1013. doi:10.1242/jcs.045112

    Article  PubMed  CAS  Google Scholar 

  39. Schweingruber N, Haine A, Tiede K, Karabinskaya A, van den Brandt J, Wüst S, Metselaar JM, Gold R, Tuckermann JP, Reichardt HM, Lühder F (2011) Liposomal encapsulation of glucocorticoids alters their mode of action in the treatment of experimental autoimmune encephalomyelitis. J Immunol 187(8):4310–4318. doi:10.4049/jimmunol.1101604

    Article  PubMed  CAS  Google Scholar 

  40. Schweingruber N, Reichardt SD, Lühder F, Reichardt HM (2012) Mechanisms of glucocorticoids in the control of neuroinflammation. J Neuroendocrinol 24(1):174–182. doi:10.1111/j.1365-2826.2011.02161.x

    Article  PubMed  CAS  Google Scholar 

  41. Siffrin V, Brandt AU, Radbruch H, Herz J, Boldakowa N, Leuenberger T, Werr J, Hahner A, Schulze-Topphoff U, Nitsch R, Zipp F (2009) Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization. Brain 132(Pt 5):1247–1258. doi:10.1093/brain/awn354

    Article  PubMed  Google Scholar 

  42. Steinman L, Zamvil SS (2006) How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis. Ann Neurol 60(1):12–21. doi:10.1002/ana.20913

    Article  PubMed  CAS  Google Scholar 

  43. Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Hollt V, Schulz S (2002) A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci 22(14):5865–5878

    PubMed  CAS  Google Scholar 

  44. Tischner D, Theiss J, Karabinskaya A, van den Brandt J, Reichardt SD, Karow U, Herold MJ, Lühder F, Utermöhlen O, Reichardt HM (2011) Acid sphingomyelinase is required for protection of effector memory T cells against glucocorticoid-induced cell death. J Immunol 187(9):4509–4516. doi:10.4049/jimmunol.1100911

    Article  PubMed  CAS  Google Scholar 

  45. Tischner D, van den Brandt J, Weishaupt A, Lühder F, Herold MJ, Reichardt HM (2009) Stable silencing of the glucocorticoid receptor in myelin-specific T effector cells by retroviral delivery of shRNA: insight into neuroinflammatory disease. Eur J Immunol 39(9):2361–2370. doi:10.1002/eji.200939490

    Article  PubMed  CAS  Google Scholar 

  46. Tischner D, Weishaupt A, van den Brandt J, Müller N, Beyersdorf N, Ip CW, Toyka KV, Hünig T, Gold R, Kerkau T, Reichardt HM (2006) Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis. Brain 129(Pt 10):2635–2647. doi:10.1093/brain/awl213

    Article  PubMed  Google Scholar 

  47. Tuckermann JP, Kleiman A, Moriggl R, Spanbroek R, Neumann A, Illing A, Clausen BE, Stride B, Förster I, Habenicht AJ, Reichardt HM, Tronche F, Schmid W, Schütz G (2007) Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy. J Clin Invest 117(5):1381–1390. doi:10.1172/JCI28034

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Uhmann A, van den Brandt J, Dittmann K, Hess I, Dressel R, Binder C, Lühder F, Christiansen H, Fassnacht M, Bhandoola A, Wienands J, Reichardt HM, Hahn H (2011) T cell development critically depends on prethymic stromal patched expression. J Immunol 186(6):3383–3391. doi:10.4049/jimmunol.1001939

    Article  PubMed  CAS  Google Scholar 

  49. Varga G, Ehrchen J, Tsianakas A, Tenbrock K, Rattenholl A, Seeliger S, Mack M, Roth J, Sunderkoetter C (2008) Glucocorticoids induce an activated, anti-inflammatory monocyte subset in mice that resembles myeloid-derived suppressor cells. J Leukoc Biol 84(3):644–650. doi:10.1189/jlb.1107768

    Article  PubMed  CAS  Google Scholar 

  50. Wüst S, Tischner D, John M, Tuckermann JP, Menzfeld C, Hanisch UK, van den Brandt J, Lühder F, Reichardt HM (2009) Therapeutic and adverse effects of a non-steroidal glucocorticoid receptor ligand in a mouse model of multiple sclerosis. PLoS One 4(12):e8202. doi:10.1371/journal.pone.0008202

    Article  PubMed Central  PubMed  Google Scholar 

  51. Wüst S, van den Brandt J, Tischner D, Kleiman A, Tuckermann JP, Gold R, Lühder F, Reichardt HM (2008) Peripheral T cells are the therapeutic targets of glucocorticoids in experimental autoimmune encephalomyelitis. J Immunol 180(12):8434–8443

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Martina Weig, Birgit Curdt, Regine Kruse, Nancy Meyer, Amina Bassibas and Julian Koch for technical assistance, Cathy Ludwig for language corrections, Jerry Adams for vav-Bcl-2 tg mice and Meike Schaffrinski and Florian Klemm for help with buffy coats. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Lu634/8-1, Tu220/3-1, FOR 1336, SFB-TRR 43/B11 & B13), the Bundesministerium für Bildung und Forschung (UNDERSTAND MS) and the Austrian Science Fund (FWF), grant Y212-B13.

Conflict of interest

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Fred Lühder or Holger M. Reichardt.

Additional information

N. Schweingruber, H. J. Fischer, L. Fischer, F. Lühder and H. M. Reichardt shared first and senior authorships.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 350 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schweingruber, N., Fischer, H.J., Fischer, L. et al. Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses. Acta Neuropathol 127, 713–729 (2014). https://doi.org/10.1007/s00401-014-1248-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-014-1248-4

Keywords

Navigation