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

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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.

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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

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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.

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Authors and Affiliations

  1. Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan

    Yasuo Uchida, Tomohito Sumiya, Masanori Tachikawa, Tatsuya Yamakawa, Sho Murata, Yuta Yagi, Kazuki Sato, Alice Stephan, Katsuaki Ito & Tetsuya Terasaki

  2. Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Sumio Ohtsuki

  3. Institut Cochin, Inserm U1016, CNRS UMR8104, Paris Descartes University, Sorbonne Paris City, Paris, France

    Pierre-Olivier Couraud

  4. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Takashi Suzuki

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  1. Yasuo Uchida
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Correspondence to Yasuo Uchida.

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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.

Electronic Supplementary Material

Supplemental data including the experimental data and the details of the materials and methods is available at Molecular Neurobiology online.

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Uchida, Y., Sumiya, T., Tachikawa, M. et al. Involvement of Claudin-11 in Disruption of Blood-Brain, -Spinal Cord, and -Arachnoid Barriers in Multiple Sclerosis. Mol Neurobiol 56, 2039–2056 (2019). https://doi.org/10.1007/s12035-018-1207-5

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