TY - JOUR
T1 - Involvement of Claudin-11 in Disruption of Blood-Brain, -Spinal Cord, and -Arachnoid Barriers in Multiple Sclerosis
AU - Uchida, Yasuo
AU - Sumiya, Tomohito
AU - Tachikawa, Masanori
AU - Yamakawa, Tatsuya
AU - Murata, Sho
AU - Yagi, Yuta
AU - Sato, Kazuki
AU - Stephan, Alice
AU - Ito, Katsuaki
AU - Ohtsuki, Sumio
AU - Couraud, Pierre Olivier
AU - Suzuki, Takashi
AU - Terasaki, Tetsuya
N1 - Funding Information:
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 Information:
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.
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - Blood-arachnoid barrier
KW - Blood-brain barrier
KW - Blood-spinal cord barrier
KW - Claudin-11
KW - Claudin-5
KW - Multiple sclerosis
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UR - http://www.scopus.com/inward/citedby.url?scp=85049579847&partnerID=8YFLogxK
U2 - 10.1007/s12035-018-1207-5
DO - 10.1007/s12035-018-1207-5
M3 - Article
C2 - 29984400
AN - SCOPUS:85049579847
SN - 0893-7648
VL - 56
SP - 2039
EP - 2056
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -