Journal of Neuroimmune Pharmacology

, Volume 9, Issue 3, pp 438–445 | Cite as

Integrin/Chemokine Receptor Interactions in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

  • Ghazal Banisadr
  • Samantha R. Schwartz
  • Joseph R. Podojil
  • Linda A. Piccinini
  • Stefan Lanker
  • Stephen D. Miller
  • Richard J. Miller
ORIGINAL ARTICLE
First Online:
Received:
Accepted:

Abstract

Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-α4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri®)) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti-VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAb was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti-VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE.

Keywords

Chemokine Chemokine receptor Anti-VLA-4 antibody Experimental autoimmune encephalomyelitis 
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Notes

Acknowledgments

This work was supported by funding from Biogen Idec and the NIH.

Conflict of interest

Authors have no conflict of interest to disclose.

References

  1. Banisadr G, Frederick TJ, Freitag C, Ren D, Jung H, Miller SD, Miller RJ (2011) The role of CXCR4 signaling in the migration of transplanted oligodendrocyte progenitors into the cerebral white matter. Neurobiology of Disease 44:19–27PubMedCentralPubMedGoogle Scholar
  2. Bhattacharyya BJ, Banisadr G, Jung H, Ren D, Cronshaw DG, Zou Y, Miller RJ (2008) The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus. J Neurosci 28:6720–6730PubMedCentralPubMedCrossRefGoogle Scholar
  3. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123(6):1174–1183PubMedCrossRefGoogle Scholar
  4. Bonig H, Watts KL, Chang KH, Kiem HP, Papayannopoulou T (2009) Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells 27(4):836–837PubMedCentralPubMedCrossRefGoogle Scholar
  5. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 354(9):942–955PubMedCrossRefGoogle Scholar
  6. Fuller KG, Olson JK, Howard LM, Croxford JL, Miller SD (2004) Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler’s virus-induced demyelinating disease. Methods Mol Med 102:339–361PubMedGoogle Scholar
  7. Glabinski AR, Tani M, Strieter RM, Tuohy VK, Ransohoff RM (1997) Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol 150(2):617–630PubMedCentralPubMedGoogle Scholar
  8. Kennedy KJ, Karpus WJ (1999) Role of chemokines in the regulation of Th1/Th2 and autoimmune encephalomyelitis. J Clin Immunol 19(5):273–279PubMedCrossRefGoogle Scholar
  9. McCandless EE, Piccio L, Woerner BM, Schmidt RE, Rubin JB, Cross AH, Klein RS (2008) Pathological expression of CXCL12 at the blood–brain barrier correlates with severity of multiple sclerosis. Am J Pathol 172:799–808PubMedCentralPubMedCrossRefGoogle Scholar
  10. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26:7907–7918PubMedCrossRefGoogle Scholar
  11. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382(6592):635–638PubMedCrossRefGoogle Scholar
  12. Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R, Baron-Van EA (2007) Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc Natl Acad Sci U S A 104:4694–4699PubMedCentralPubMedCrossRefGoogle Scholar
  13. Ngo HT, Leleu X, Lee J, Jia X, Melhem M, Runnels J, Moreau AS, Burwick N, Azab AK, Roccaro A, Azab F, Sacco A, Farag M, Sackstein R, Ghobrial IM (2008) SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. Blood 112(1):150–158PubMedCentralPubMedCrossRefGoogle Scholar
  14. Petty JM, Lenox CC, Weiss DJ, Poynter ME, Suratt BT (2009) Crosstalk between CXCR4/stromal derived factor-1 and VLA-4/VCAM-1 pathways regulates neutrophil retention in the bone marrow. J Immunol 182(1):604–612PubMedCentralPubMedCrossRefGoogle Scholar
  15. Pluchino S, Martino G (2005) The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci 233:117–119PubMedCrossRefGoogle Scholar
  16. Tran PB, Banisadr G, Ren D, Chenn A, Miller RJ (2007) Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain. J Comp Neurol 500(6):1007–1033Google Scholar
  17. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285PubMedCrossRefGoogle Scholar
  18. Zohren F, Toutzaris D, Klärner V, Hartung HP, Kieseier B, Haas R (2008) The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 111:3893–3895PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Ghazal Banisadr
    • 1
    • 4
  • Samantha R. Schwartz
    • 1
  • Joseph R. Podojil
    • 2
  • Linda A. Piccinini
    • 3
  • Stefan Lanker
    • 3
  • Stephen D. Miller
    • 2
  • Richard J. Miller
    • 1
  1. 1.Department of Molecular Pharmacology and Biological ChemistryNorthwestern University Medical SchoolChicagoUSA
  2. 2.Dept of Microbiology-ImmunologyNorthwestern University Medical SchoolChicagoUSA
  3. 3.Biogen IdecCambridgeUSA
  4. 4.Department of Molecular Pharmacology and Biological ChemistryNorthwestern University Feinberg School of MedicineChicagoUSA

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