Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A role for leukocyte-endothelial adhesion mechanisms in epilepsy

Abstract

The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1,2,3. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins α4β1 and αLβ2. Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: α4 integrin, VCAM-1 and PSGL-1 dependence of PMN and TH1 cell interactions with brain endothelium after status epilepticus.
Figure 2: Effect of blockade or deficiency in leukocyte adhesion mechanisms on convulsions and seizures.
Figure 3: Effect of blockade or deficiency in leukocyte adhesion mechanisms on CNS structure and neuronal density.
Figure 4: Inhibition or deficiency of leukocyte adhesion pathways maintains the integrity of the BBB.

Similar content being viewed by others

References

  1. Strzelczyk, A., Reese, J.P., Dodel, R. & Hamer, H.M. Cost of epilepsy: a systematic review. Pharmacoeconomics 26, 463–476 (2008).

    Article  Google Scholar 

  2. Holmes, G.L. Seizure-induced neuronal injury: animal data. Neurology 59, S3–S6 (2002).

    Article  Google Scholar 

  3. Duncan, J.S. Seizure-induced neuronal injury: human data. Neurology 59, S15–S20 (2002).

    Article  Google Scholar 

  4. Vezzani, A. Inflammation and epilepsy. Epilepsy Curr. 5, 1–6 (2005).

    Article  Google Scholar 

  5. Vezzani, A. & Granata, T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46, 1724–1743 (2005).

    Article  CAS  Google Scholar 

  6. Seiffert, E. et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J. Neurosci. 24, 7829–7836 (2004).

    Article  CAS  Google Scholar 

  7. Ivens, S. et al. TGF-β receptor–mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535–547 (2007).

    Article  Google Scholar 

  8. Van Vliet, E.A. et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 130, 521–534 (2007).

    Article  CAS  Google Scholar 

  9. Marchi, N. et al. In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia 48, 1934–1946 (2007).

    Article  CAS  Google Scholar 

  10. Luster, A.D., Alon, R. & von Andrian, U.H. Immune cell migration in inflammation: present and future therapeutic targets. Nat. Immunol. 6, 1182–1190 (2005).

    Article  CAS  Google Scholar 

  11. Ransohoff, R.M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581 (2003).

    Article  CAS  Google Scholar 

  12. Shibley, H. & Smith, B.N. Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice. Epilepsy Res. 49, 109–120 (2002).

    Article  CAS  Google Scholar 

  13. Gröticke, I., Hoffmann, K. & Löscher, W. Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice. Exp. Neurol. 207, 329–349 (2007).

    Article  Google Scholar 

  14. Fabene, P.F., Marzola, P., Sbarbati, A. & Bentivoglio, M. Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps and direct correlation with tissue and cell damage. Neuroimage 18, 375–389 (2003).

    Article  CAS  Google Scholar 

  15. Piccio, L. et al. Molecular mechanisms involved in lymphocyte recruitment in brain microcirculation: critical roles for PSGL-1 and trimeric Gαi linked receptors. J. Immunol. 168, 1940–1949 (2002).

    Article  CAS  Google Scholar 

  16. Glien, M. et al. Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy. Epilepsy Res. 46, 111–119 (2001).

    Article  CAS  Google Scholar 

  17. Klitgaard, H., Matagne, A., Veneste-Goemaere, J. & Margineanu, D.G. Pilocarpine-induced epileptogenesis in the rat: impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations. Epilepsy Res. 51, 93–107 (2002).

    Article  CAS  Google Scholar 

  18. Racine, R.J. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr. Clin. Neurophysiol. 32, 281–294 (1972).

    Article  CAS  Google Scholar 

  19. Ley, K. & Kansas, G.S. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat. Rev. Immunol. 4, 325–335 (2004).

    Article  CAS  Google Scholar 

  20. Ley, K., Laudanna, C., Cybulsky, M.I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  21. Oby, E. & Janigro, D. The blood-brain barrier and epilepsy. Epilepsia 47, 1761–1774 (2006).

    Article  CAS  Google Scholar 

  22. Lebwohl, M. et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl. J. Med. 349, 2004–2013 (2003).

    Article  CAS  Google Scholar 

  23. Polman, C.H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

    Article  CAS  Google Scholar 

  24. Maly, P. et al. The alpha(1,3)fucosyltransferase Fuc-TVII controls leukocyte trafficking through an essential role in L-, E- and P-selectin ligand biosynthesis. Cell 86, 643–653 (1996).

    Article  CAS  Google Scholar 

  25. Homeister, J.W. et al. The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing. Immunity 15, 115–126 (2001).

    Article  CAS  Google Scholar 

  26. Xia, L. et al. P-selectin glycoprotein ligand-1–deficient mice have impaired leukocyte tethering to E-selectin under flow. J. Clin. Invest. 109, 939–950 (2002).

    Article  CAS  Google Scholar 

  27. Runge, V.M. et al. The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption. Magn. Reson. Imaging 3, 43–55 (1985).

    Article  CAS  Google Scholar 

  28. Lowell, C.A., Fumagalli, L. & Berton, G. Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions. J. Cell Biol. 133, 895–910 (1996).

    Article  CAS  Google Scholar 

  29. Battistini, L. et al. CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1. Blood 101, 4775–4782 (2003).

    Article  CAS  Google Scholar 

  30. Constantin, G. et al. Chemokines trigger immediate β2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. Immunity 13, 759–769 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Antibody to PSGL-1 (4RA10) was kindly provided by D. Vestweber, Max Plank Institute. We wish to thank C. Laudanna for critically discussing the manuscript. This work was supported in part by grants from the Fondazione Cariverona, Ministero dell'Università e della Ricerca (MIUR)–Progetti di ricerca di interese nazionale, the US National Multiple Sclerosis Society, Fondo Incentivazione Ricerca di Base, the Italian Ministry of Health; Fondazione Italiana Sclerosi Multipla, the University of Verona ex 60% MIUR (to G.C.); the European Community Research Grants LSH-CT-2006-037315 (EPICURE, thematic priority LIFESCIHEALTH; University of Verona ex 60% MIUR (to P.F.F.); and by US National Institutes of Health grants (to E.C.B., L.X., R.P.M. and J.B.L.). L.O. was supported in part by a fellowship from Fondazione Italiana Sclerosi Multipla. The authors are grateful to S. Fiorini, I. Cwojdzinski, P. Bernardi, M. Pellitteri, S. Becchi, L. Andrello and A. Calbi for their invaluable help in the experimental procedures.

Author information

Authors and Affiliations

Authors

Contributions

G.N.M., D.B., A.C., L.Z. and F.S. performed epilepsy experiments, telemetry and open field behavior. M.M., B.R., L.O., S.B. and S.A. performed intravital microscopy, in vivo staining for adhesion molecules, adhesion assays and contributed to obtaining the behavioral data. A.O. provided the human samples. F.M., A.C. and F.O. performed immunohistochemistry on human and animal samples. P.M., E.N. and A.S. provided MRI expertise. J.W.H., L.X., J.B.L. and R.P.M. provided key reagents and mice. E.C.B. contributed experimental suggestions, reagents and assistance with writing. P.F.F. and G.C. designed the study, analyzed the data and wrote the paper.

Corresponding authors

Correspondence to Paolo F Fabene or Gabriela Constantin.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4, Supplementary Tables 1–3, Supplementary Methods and Supplementary Discussion (PDF 587 kb)

Supplementary Video 1

This movie shows SE-induction in WT mice after pilocarpine administration paralleled by the normal behavior of mice lacking fucosyltransferase (FucT)-VII activity (MOV 2391 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fabene, P., Mora, G., Martinello, M. et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 14, 1377–1383 (2008). https://doi.org/10.1038/nm.1878

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1878

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing