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Involvement of Claudin-11 in Disruption of Blood-Brain, -Spinal Cord, and -Arachnoid Barriers in Multiple Sclerosis

  • Yasuo Uchida
  • Tomohito Sumiya
  • Masanori Tachikawa
  • Tatsuya Yamakawa
  • Sho Murata
  • Yuta Yagi
  • Kazuki Sato
  • Alice Stephan
  • Katsuaki Ito
  • Sumio Ohtsuki
  • Pierre-Olivier Couraud
  • Takashi Suzuki
  • Tetsuya Terasaki
Article

Abstract

It is important to understand the molecular mechanisms of barrier disruption in the central nervous system (CNS) of patients with multiple sclerosis (MS). The purpose of the present study was to clarify whether claudin-11 is involved in the disruption of two endothelial barriers (blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB)) and two epithelial barriers (blood-arachnoid barrier (BAB) and blood-CSF barrier (BCSFB)) in the CNS in MS. Immunohistochemical analysis revealed that, in both normal human and mouse, claudin-11 is co-localized with claudin-5 in the brain and spinal cord capillaries. The absolute protein expression level of claudin-11 was nearly equal to that of claudin-5 in rat brain capillaries, but was 2.81-fold greater in human brain capillaries. The protein expressions of claudin-11 were significantly downregulated in the brain and spinal cord capillaries of an MS patient and experimental autoimmune encephalomyelitis (EAE) mice. Specific downregulation of claudin-11 with siRNA significantly increased the transfer of membrane-impermeable FITC-dextran across human brain capillary endothelial cell (hCMEC/D3) monolayer. As for the epithelial barrier, claudin-11 protein expression was not decreased in choroid plexus epithelial cells forming the BCSFB in EAE mice, whereas it was decreased in brain and spinal cord meninges that form the BAB. Specific downregulation of claudin-11 with siRNA in a rat choroid plexus epithelial cell (TR-CSFB) monolayer significantly increased the permeability of FITC-dextran. In conclusion, our present findings indicate that claudin-11 expression at the BBB, BSCB, and BAB, but not the BCSFB, is downregulated in multiple sclerosis, impairing the functional integrity of these barriers.

Keywords

Claudin-11 Claudin-5 Multiple sclerosis Blood-spinal cord barrier Blood-arachnoid barrier Blood-brain barrier 

Abbreviations

BAB

Blood-arachnoid barrier

BBB

Blood-brain barrier

BCSFB

Blood-cerebrospinal fluid barrier

B-cap

Brain capillary

BSCB

Blood-spinal cord barrier

DDA

Data-dependent acquisition

DHT

Dihydrotestosterone

EAE

Experimental autoimmune encephalomyelitis

ER-TR7

A meningeal marker

Glut1

Glucose transporter 1

hCMEC/D3

Human cerebral microvascular endothelial cell line

LC-MS/MS

Liquid chromatography–tandem mass spectrometry

MS

Multiple sclerosis

PRM

Parallel reaction monitoring

QTAP

Quantitative targeted absolute proteomics

SC-cap

Spinal cord capillary

SRM

Selected reaction monitoring

TM-BBB

Mouse brain capillary endothelial cell line

TR-CSFB

Rat choroid plexus epithelial cell line

Notes

Acknowledgements

We thank Prof Koji Fukunaga (Graduate School of Pharmaceutical Sciences, Tohoku University, Japan) for making available the confocal laser-scanning microscope, and A. Niitomi and N. Handa for their secretarial assistance.

Funding

This study was supported in part by three Grants-in-Aids from the Japanese Society for the Promotion of Science (JSPS) for Challenging Exploratory Research (KAKENHI 16K15475), Young Scientists (A) (KAKENHI 16H06218), and Scientific Research (B) (KAKENHI 17H04004), and was also supported in part by the Nakatomi Foundation.

Compliance with Ethical Standards

Conflicts of Interest

Tetsuya Terasaki and Sumio Ohtsuki are full professors at Tohoku University and Kumamoto University, and are also directors of Proteomedix Frontiers Co., Ltd. This study was not supported by Proteomedix Frontiers Co., Ltd., and their positions at Proteomedix Frontiers Co., Ltd., did not influence the design of the study, the collection of data, the analysis or interpretation of data, the decision to submit the manuscript for publication, or writing of the manuscript. There were no financial conflicts. The other authors declare no competing interests.

Supplementary material

12035_2018_1207_MOESM1_ESM.pdf (701 kb)
ESM 1 (PDF 700 kb)

References

  1. 1.
    Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, Rudge P et al (1990) Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 113(Pt 5):1477–1489CrossRefPubMedGoogle Scholar
  2. 2.
    Errede M, Girolamo F, Ferrara G, Strippoli M, Morando S, Boldrin V, Rizzi M, Uccelli A et al (2012) Blood-brain barrier alterations in the cerebral cortex in experimental autoimmune encephalomyelitis. J Neuropathol Exp Neurol 71(10):840–854.  https://doi.org/10.1097/NEN.0b013e31826ac110 CrossRefPubMedGoogle Scholar
  3. 3.
    Kooij G, Kopplin K, Blasig R, Stuiver M, Koning N, Goverse G, van der Pol SM, van Het Hof B et al (2014) Disturbed function of the blood-cerebrospinal fluid barrier aggravates neuro-inflammation. Acta Neuropathol 128(2):267–277.  https://doi.org/10.1007/s00401-013-1227-1 CrossRefPubMedGoogle Scholar
  4. 4.
    Hellani A, Ji J, Mauduit C, Deschildre C, Tabone E, Benahmed M (2000) Developmental and hormonal regulation of the expression of oligodendrocyte-specific protein/claudin 11 in mouse testis. Endocrinology 141(8):3012–3019.  https://doi.org/10.1210/endo.141.8.7625 CrossRefPubMedGoogle Scholar
  5. 5.
    Tiwari-Woodruff SK, Buznikov AG, Vu TQ, Micevych PE, Chen K, Kornblum HI, Bronstein JM (2001) OSP/claudin-11 forms a complex with a novel member of the tetraspanin super family and beta1 integrin and regulates proliferation and migration of oligodendrocytes. J Cell Biol 153(2):295–305CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Brochner CB, Holst CB, Mollgard K (2015) Outer brain barriers in rat and human development. Front Neurosci 9:75.  https://doi.org/10.3389/fnins.2015.00075 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Romanitan MO, Popescu BO, Spulber S, Bajenaru O, Popescu LM, Winblad B, Bogdanovic N (2010) Altered expression of claudin family proteins in Alzheimer's disease and vascular dementia brains. J Cell Mol Med 14(5):1088–1100.  https://doi.org/10.1111/j.1582-4934.2009.00999.x PubMedCrossRefGoogle Scholar
  8. 8.
    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):77–80CrossRefPubMedGoogle Scholar
  9. 9.
    Florin A, Maire M, Bozec A, Hellani A, Chater S, Bars R, Chuzel F, Benahmed M (2005) Androgens and postmeiotic germ cells regulate claudin-11 expression in rat Sertoli cells. Endocrinology 146(3):1532–1540.  https://doi.org/10.1210/en.2004-0834 CrossRefPubMedGoogle Scholar
  10. 10.
    Kaitu'u-Lino TJ, Sluka P, Foo CF, Stanton PG (2007) Claudin-11 expression and localisation is regulated by androgens in rat Sertoli cells in vitro. Reproduction 133(6):1169–1179.  https://doi.org/10.1530/REP-06-0385 CrossRefPubMedGoogle Scholar
  11. 11.
    Tomassini V, Onesti E, Mainero C, Giugni E, Paolillo A, Salvetti M, Nicoletti F, Pozzilli C (2005) Sex hormones modulate brain damage in multiple sclerosis: MRI evidence. J Neurol Neurosurg Psychiatry 76(2):272–275.  https://doi.org/10.1136/jnnp.2003.033324 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhu ML, Bakhru P, Conley B, Nelson JS, Free M, Martin A, Starmer J, Wilson EM et al (2016) Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun 7:11350.  https://doi.org/10.1038/ncomms11350 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Prockop LD, Naidu KA, Binard JE, Ransohoff J (1995) Selective permeability of [3H]-D-mannitol and [14C]-carboxyl-inulin across the blood-brain barrier and blood-spinal cord barrier in the rabbit. J Spinal Cord Med 18(4):221–226CrossRefPubMedGoogle Scholar
  14. 14.
    Schlaeger R, Papinutto N, Zhu AH, Lobach IV, Bevan CJ, Bucci M, Castellano A, Gelfand JM et al (2015) Association between thoracic spinal cord gray matter atrophy and disability in multiple sclerosis. JAMA Neurol 72(8):897–904.  https://doi.org/10.1001/jamaneurol.2015.0993 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Winkler EA, Sengillo JD, Bell RD, Wang J, Zlokovic BV (2012) Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability. J Cereb Blood Flow Metab 32(10):1841–1852.  https://doi.org/10.1038/jcbfm.2012.113 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Schlager C, Korner H, Krueger M, Vidoli S, Haberl M, Mielke D, Brylla E, Issekutz T et al (2016) Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530(7590):349–353.  https://doi.org/10.1038/nature16939 CrossRefPubMedGoogle Scholar
  17. 17.
    Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A et al (2005) Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872–1874.  https://doi.org/10.1096/fj.04-3458fje CrossRefPubMedGoogle Scholar
  18. 18.
    Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T (2011) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117(2):333–345CrossRefPubMedGoogle Scholar
  19. 19.
    Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T (2013) Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci 102(9):3343–3355.  https://doi.org/10.1002/jps.23575 CrossRefPubMedGoogle Scholar
  20. 20.
    Kamiie J, Ohtsuki S, Iwase R, Ohmine K, Katsukura Y, Yanai K, Sekine Y, Uchida Y et al (2008) Quantitative atlas of membrane transporter proteins: development and application of a highly sensitive simultaneous LC/MS/MS method combined with novel in-silico peptide selection criteria. Pharm Res 25(6):1469–1483CrossRefPubMedGoogle Scholar
  21. 21.
    Uchida Y, Ohtsuki S, Kamiie J, Terasaki T (2011) Blood-brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice. J Pharmacol Exp Ther 339(2):579–588.  https://doi.org/10.1124/jpet.111.184200 CrossRefPubMedGoogle Scholar
  22. 22.
    Morgan L, Shah B, Rivers LE, Barden L, Groom AJ, Chung R, Higazi D, Desmond H et al (2007) Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis. Neuroscience 147(3):664–673.  https://doi.org/10.1016/j.neuroscience.2007.04.051 CrossRefPubMedGoogle Scholar
  23. 23.
    Ohtsuki S, Yamaguchi H, Katsukura Y, Asashima T, Terasaki T (2008) mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting. J Neurochem 104(1):147–154.  https://doi.org/10.1111/j.1471-4159.2007.05008.x PubMedCrossRefGoogle Scholar
  24. 24.
    Gong Y, Renigunta V, Zhou Y, Sunq A, Wang J, Yang J, Renigunta A, Baker LA et al (2015) Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization. Mol Biol Cell 26(24):4333–4346.  https://doi.org/10.1091/mbc.E15-06-0422 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Hou J, Renigunta A, Yang J, Waldegger S (2010) Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization. Proc Natl Acad Sci U S A 107(42):18010–18015.  https://doi.org/10.1073/pnas.1009399107 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Uchida Y, Zhang Z, Tachikawa M, Terasaki T (2015) Quantitative targeted absolute proteomics of rat blood-cerebrospinal fluid barrier transporters: comparison with a human specimen. J Neurochem 134(6):1104–1115.  https://doi.org/10.1111/jnc.13147 CrossRefPubMedGoogle Scholar
  27. 27.
    Kolias AG, Chari A, Santarius T, Hutchinson PJ (2014) Chronic subdural haematoma: modern management and emerging therapies. Nat Rev Neurol 10(10):570–578.  https://doi.org/10.1038/nrneurol.2014.163 CrossRefPubMedGoogle Scholar
  28. 28.
    Thorne RG (2014) Primer on central nervous system structure/function and the vasculature, ventricular system, and fluids of the brai. In: Hammarlund-Udenaes M, de Lange E, Thorne RG (eds) Drug delivery to the brain - physiological concepts, methodologies and approaches. Springer, pp. 685–707Google Scholar
  29. 29.
    Lui WY, Lee WM (2009) Molecular mechanisms by which hormones and cytokines regulate cell junction dynamics in the testis. J Mol Endocrinol 43(2):43–51.  https://doi.org/10.1677/JME-08-0174 CrossRefPubMedGoogle Scholar
  30. 30.
    Yan HH, Mruk DD, Lee WM, Cheng CY (2008) Blood-testis barrier dynamics are regulated by testosterone and cytokines via their differential effects on the kinetics of protein endocytosis and recycling in Sertoli cells. FASEB J 22(6):1945–1959.  https://doi.org/10.1096/fj.06-070342 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lanz TV, Becker S, Osswald M, Bittner S, Schuhmann MK, Opitz CA, Gaikwad S, Wiestler B et al (2013) Protein kinase Cbeta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 110(36):14735–14740.  https://doi.org/10.1073/pnas.1302569110 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161(3):653–660.  https://doi.org/10.1083/jcb.200302070 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yasuo Uchida
    • 1
  • Tomohito Sumiya
    • 1
  • Masanori Tachikawa
    • 1
  • Tatsuya Yamakawa
    • 1
  • Sho Murata
    • 1
  • Yuta Yagi
    • 1
  • Kazuki Sato
    • 1
  • Alice Stephan
    • 1
  • Katsuaki Ito
    • 1
  • Sumio Ohtsuki
    • 2
  • Pierre-Olivier Couraud
    • 3
  • Takashi Suzuki
    • 4
  • Tetsuya Terasaki
    • 1
  1. 1.Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
  2. 2.Faculty of Life SciencesKumamoto UniversityKumamotoJapan
  3. 3.Institut Cochin, Inserm U1016, CNRS UMR8104Paris Descartes UniversityParisFrance
  4. 4.Department of Pathology and HistotechnologyTohoku University Graduate School of MedicineSendaiJapan

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