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


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.


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



Blood-arachnoid barrier


Blood-brain barrier


Blood-cerebrospinal fluid barrier


Brain capillary


Blood-spinal cord barrier


Data-dependent acquisition




Experimental autoimmune encephalomyelitis


A meningeal marker


Glucose transporter 1


Human cerebral microvascular endothelial cell line


Liquid chromatography–tandem mass spectrometry


Multiple sclerosis


Parallel reaction monitoring


Quantitative targeted absolute proteomics


Spinal cord capillary


Selected reaction monitoring


Mouse brain capillary endothelial cell line


Rat choroid plexus epithelial cell line



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.


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)


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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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