Skip to main content

Advertisement

SpringerLink
Log in

Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation

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

Abstract

Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood–cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.

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

Access this article

Log in via an institution

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

Similar content being viewed by others

References

  1. Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonniere L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A (2011) The hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science 334(6063):1727–1731

    Article  PubMed  CAS  Google Scholar 

  2. Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R, Dijkstra CD, van der Valk P, Bo L (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63(1):16–25

    Article  PubMed  CAS  Google Scholar 

  3. Cepok S, Jacobsen M, Schock S, Omer B, Jaekel S, Boddeker I, Oertel WH, Sommer N, Hemmer B (2001) Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis. Brain 124(Pt 11):2169–2176

    Article  PubMed  CAS  Google Scholar 

  4. Coisne C, Engelhardt B (2011) Tight junctions in brain barriers during central nervous system inflammation. Antioxid Redox Signal 15(5):1285–1303

    Article  PubMed  CAS  Google Scholar 

  5. Daneman R, Zhou L, Agalliu D, Cahoy JD, Kaushal A, Barres BA (2010) The mouse blood–brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS ONE 5(10):e13741

    Article  PubMed  PubMed Central  Google Scholar 

  6. Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med 354(9):942–955

    Article  PubMed  CAS  Google Scholar 

  7. Garcia-Vallejo JJ, Van Het HB, Robben J, Van Wijk JA, Van Die I, Joziasse DH, Van Dijk W (2004) Approach for defining endogenous reference genes in gene expression experiments. Anal Biochem 329(2):293–299

    Article  PubMed  CAS  Google Scholar 

  8. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination. J Pathol 201(2):319–327

    Article  PubMed  Google Scholar 

  9. Kooi EJ, Prins M, Bajic N, Belien JA, Gerritsen WH, van Horssen J, Aronica E, van Dam AM, Hoozemans JJ, Francis PT, van der Valk P, Geurts JJ (2011) Cholinergic imbalance in the multiple sclerosis hippocampus. Acta Neuropathol 122(3):313–322

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Kooij G, Backer R, Koning JJ, Reijerkerk A, van Horssen J, van der Pol SM, Drexhage J, Schinkel A, Dijkstra CD, den Haan JM, Geijtenbeek TB, de Vries HE (2009) P-glycoprotein acts as an immunomodulator during neuroinflammation. PLoS ONE 4(12):e8212

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kooij G, Mizee MR, van Horssen J, Reijerkerk A, Witte ME, Drexhage JA, van der Pol SM, Van Het HB, Scheffer G, Scheper R, Dijkstra CD, Van der Valk P, de Vries HE (2011) Adenosine triphosphate-binding cassette transporters mediate chemokine (C–C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. Brain 134(Pt 2):555–570

    Article  PubMed  Google Scholar 

  12. Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE (2008) Structure and function of claudins. Biochim Biophys Acta 1778(3):631–645

    Article  PubMed  CAS  Google Scholar 

  13. Kuijk LM, Klaver EJ, Kooij G, van der Pol SM, Heijnen P, Bruijns SC, Kringel H, Pinelli E, Kraal G, de Vries HE, Dijkstra CD, Bouma G, van Die I (2012) Soluble helminth products suppress clinical signs in murine experimental autoimmune encephalomyelitis and differentially modulate human dendritic cell activation. Mol Immunol 51(2):210–218

    Article  PubMed  CAS  Google Scholar 

  14. Li Q, Zhang Q, Wang C, Liu X, Qu L, Gu L, Li N, Li J (2009) Altered distribution of tight junction proteins after intestinal ischaemia/reperfusion injury in rats. J Cell Mol Med 13(9B):4061–4076

    Article  PubMed  Google Scholar 

  15. Liu P, Jenkins NA, Copeland NG (2003) A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res 13(3):476–484

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, Bruck W, Parisi JE, Scheithauer BW, Giannini C, Weigand SD, Mandrekar J, Ransohoff RM (2011) Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 365(23):2188–2197

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Marques F, Sousa JC, Coppola G, Falcao AM, Rodrigues AJ, Geschwind DH, Sousa N, Correia-Neves M, Palha JA (2009) Kinetic profile of the transcriptome changes induced in the choroid plexus by peripheral inflammation. J Cereb Blood Flow Metab 29(5):921–932

    Article  PubMed  CAS  Google Scholar 

  18. Marques F, Sousa JC, Coppola G, Gao F, Puga R, Brentani H, Geschwind DH, Sousa N, Correia-Neves M, Palha JA (2011) Transcriptome signature of the adult mouse choroid plexus. Fluids Barriers CNS 8(1):10

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mosley RL, Hutter-Saunders JA, Stone DK, Gendelman HE (2012) Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb Perspect Med 2(1):a009381

    Article  PubMed  PubMed Central  Google Scholar 

  20. Murugesan N, Paul D, Lemire Y, Shrestha B, Ge S, Pachter JS (2012) Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus. Fluids Barriers CNS 9(1):15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Ransohoff RM (2009) Immunology: in the beginning. Nature 462(7269):41–42

    Article  PubMed  CAS  Google Scholar 

  22. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635

    Article  PubMed  CAS  Google Scholar 

  23. 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

    Article  PubMed  CAS  Google Scholar 

  24. Reijerkerk A, Kooij G, van der Pol SM, Khazen S, Dijkstra CD, de Vries HE (2006) Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells. FASEB J 20(14):2550–2552

    Article  PubMed  CAS  Google Scholar 

  25. Reijerkerk A, Lopez-Ramirez MA, Van Het HB, Drexhage JA, Kamphuis WW, Kooij G, Vos JB, van der Pouw Kraan TC, van Zonneveld AJ, Horrevoets AJ, Prat A, Romero IA, de Vries HE (2013) MicroRNAs regulate human brain endothelial cell-barrier function in inflammation: implications for multiple sclerosis. J Neurosci 33(16):6857–6863

    Article  PubMed  CAS  Google Scholar 

  26. Robinson AM, Dorta-Contreras AJ, Lorigados PL (2001) Immune events in central nervous system of early and late onset Alzheimer’s disease patients. Rev Neurol 32(10):901–904

    Google Scholar 

  27. Schreibelt G, Kooij G, Reijerkerk A, van Doorn R, Gringhuis SI, van der Pol S, Weksler BB, Romero IA, Couraud PO, Piontek J, Blasig IE, Dijkstra CD, Ronken E, de Vries HE (2007) Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase, and PKB signaling. FASEB J 21:3666–3676

    Article  PubMed  CAS  Google Scholar 

  28. Song F, Wardrop RM, Gienapp IE, Stuckman SS, Meyer AL, Shawler T, Whitacre CC (2008) The Peyer’s patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomyelitis (EAE). J Autoimmun 30(4):230–237

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B (1996) ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am J Pathol 148(6):1819–1838

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Vercellino M, Votta B, Condello C, Piacentino C, Romagnolo A, Merola A, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P (2008) Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. J Neuroimmunol 199(1–2):133–141

    Article  PubMed  CAS  Google Scholar 

  31. Willnow TE, Herz J (1994) Homologous recombination for gene replacement in mouse cell lines. Methods Cell Biol 43(Pt A):305–334

    Article  PubMed  CAS  Google Scholar 

  32. Wilson K (2001) Preparation of genomic DNA from bacteria. Current Protocols in Molecular Biology, Chapter 2, Unit 2.4. Wiley

  33. Wolburg H, Paulus W (2010) Choroid plexus: biology and pathology. Acta Neuropathol 119(1):75–88

    Article  PubMed  Google Scholar 

  34. Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B (2001) Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett 307(2):77–80

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Netherlands Organization of Scientific Research (854.10.005 to G. Goverse), the Dutch foundation of Multiple Sclerosis Research (grant MS 12-791, G. Kooij; grant MS 05-567, J. Drexhage; grant 08-642, A. Reijkerkerk), and the Deutsche Forschungsgemeinschaft BL 308/7-4 as well as BL 308/9-1. M. Stuiver, I. C. Meij and D. Müller were supported through a grant by the European Community, FP7 (EUNEFRON 201590). We thank the Netherlands Brain Bank (www.brainbank.nl) for providing the human tissues and Kerstin Sommer for her excellent technical support.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands

    Gijs Kooij, Nathalie Koning, Gera Goverse, Susanne M. A. van der Pol, Bert van het Hof, Joost A. R. Drexhage, Arie Reijerkerk, Reina Mebius & Helga E. de Vries

  2. Department of Pediatric Nephrology, Charité Universitätsmedizin, Berlin, Germany

    Kathrin Kopplin, Marchel Stuiver & Dominik Müller

  3. Department of Molecular Cell Physiology, Leibniz-Institut für Molekulare Pharmakologie (FMP), Forschungsverbund Berlin, e.V, 13125, Berlin-Buch, Germany

    Rosel Blasig & Ingolf E. Blasig

  4. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Maik Gollasch, Iwan C. Meij & Thomas E. Willnow

  5. Medical Clinic for Nephrology and Internal Intensive Care, Charité Universitätsmedizin and Experimental and Clinical Research Center (ECRC), Berlin, Germany

    Maik Gollasch

Authors
  1. Gijs Kooij
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathrin Kopplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rosel Blasig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marchel Stuiver
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nathalie Koning
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gera Goverse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susanne M. A. van der Pol
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bert van het Hof
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maik Gollasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joost A. R. Drexhage
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Arie Reijerkerk
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Iwan C. Meij
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Reina Mebius
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Thomas E. Willnow
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dominik Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ingolf E. Blasig
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Helga E. de Vries
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gijs Kooij.

Additional information

G. Kooij, K. Kopplin and R. Blasig contributed equally.

D. Müller and I. E. Blasig contributed equally.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kooij, G., Kopplin, K., Blasig, R. et al. Disturbed function of the blood–cerebrospinal fluid barrier aggravates neuro-inflammation. Acta Neuropathol 128, 267–277 (2014). https://doi.org/10.1007/s00401-013-1227-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-013-1227-1

Keywords

Search

Navigation