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

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2039-2056
Number of pages18
JournalMolecular Neurobiology
Volume56
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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