TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier

Delphine Stephan, Oualid Sbai, Jing Wen, Pierre Olivier Couraud, Chaim Putterman, Michel Khrestchatisky, Sophie Desplat-Jégo

Research output: Contribution to journalArticle

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Abstract

Background: The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells.Methods: In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model.Results: We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model.Conclusions: Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.

Original languageEnglish (US)
Article number9
JournalJournal of Neuroinflammation
Volume10
DOIs
StatePublished - Jan 15 2013

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Blood-Brain Barrier
Endothelial Cells
Matrix Metalloproteinase 9
Personnel Selection
Brain
Cell Adhesion Molecules
Encephalitis
Astrocytes
Multiple Sclerosis
Permeability
Central Nervous System
Animal Models
Cell Culture Techniques
Pathology
Cytokines
Ligands
Membranes

Keywords

  • CCL-2
  • hCMEC/D3
  • HMEC
  • IL-8
  • MMP-9
  • Neuroinflammation
  • TNFSF12
  • ZO-1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. / Stephan, Delphine; Sbai, Oualid; Wen, Jing; Couraud, Pierre Olivier; Putterman, Chaim; Khrestchatisky, Michel; Desplat-Jégo, Sophie.

In: Journal of Neuroinflammation, Vol. 10, 9, 15.01.2013.

Research output: Contribution to journalArticle

Stephan, Delphine ; Sbai, Oualid ; Wen, Jing ; Couraud, Pierre Olivier ; Putterman, Chaim ; Khrestchatisky, Michel ; Desplat-Jégo, Sophie. / TWEAK/Fn14 pathway modulates properties of a human microvascular endothelial cell model of blood brain barrier. In: Journal of Neuroinflammation. 2013 ; Vol. 10.
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AU - Stephan, Delphine

AU - Sbai, Oualid

AU - Wen, Jing

AU - Couraud, Pierre Olivier

AU - Putterman, Chaim

AU - Khrestchatisky, Michel

AU - Desplat-Jégo, Sophie

PY - 2013/1/15

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AB - Background: The TNF ligand family member TWEAK exists as membrane and soluble forms and is involved in the regulation of various human inflammatory pathologies, through binding to its main receptor, Fn14. We have shown that the soluble form of TWEAK has a pro-neuroinflammatory effect in an animal model of multiple sclerosis and we further demonstrated that blocking TWEAK activity during the recruitment phase of immune cells across the blood brain barrier (BBB) was protective in this model. It is now well established that endothelial cells in the periphery and astrocytes in the central nervous system (CNS) are targets of TWEAK. Moreover, it has been shown by others that, when injected into mice brains, TWEAK disrupts the architecture of the BBB and induces expression of matrix metalloproteinase-9 (MMP-9) in the brain. Nevertheless, the mechanisms involved in such conditions are complex and remain to be explored, especially because there is a lack of data concerning the TWEAK/Fn14 pathway in microvascular cerebral endothelial cells.Methods: In this study, we used human cerebral microvascular endothelial cell (HCMEC) cultures as an in vitro model of the BBB to study the effects of soluble TWEAK on the properties and the integrity of the BBB model.Results: We showed that soluble TWEAK induces an inflammatory profile on HCMECs, especially by promoting secretion of cytokines, by modulating production and activation of MMP-9, and by expression of cell adhesion molecules. We also demonstrated that these effects of TWEAK are associated with increased permeability of the HCMEC monolayer in the in vitro BBB model.Conclusions: Taken together, the data suggest a role for soluble TWEAK in BBB inflammation and in the promotion of BBB interactions with immune cells. These results support the contention that the TWEAK/Fn14 pathway could contribute at least to the endothelial steps of neuroinflammation.

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