EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model
Changes in the function of the blood-brain barrier (BBB) are one of the hallmarks of multiple sclerosis (MS) and are observed at very early stages of the disease. Several disease-modifying therapies for MS regulate tight junction and adherence junction proteins in the BBB thus limiting the entry of...
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Elsevier
2025-08-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354625001036 |
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| author | Fionä Caratis Inez Mruk Klaudia Konieczna-Wolska Bartłomiej Rojek Marek Hałas Paulina Czaplewska Bartosz Karaszewski Tomomi Furihata Aleksandra Rutkowska |
| author_facet | Fionä Caratis Inez Mruk Klaudia Konieczna-Wolska Bartłomiej Rojek Marek Hałas Paulina Czaplewska Bartosz Karaszewski Tomomi Furihata Aleksandra Rutkowska |
| author_sort | Fionä Caratis |
| collection | DOAJ |
| description | Changes in the function of the blood-brain barrier (BBB) are one of the hallmarks of multiple sclerosis (MS) and are observed at very early stages of the disease. Several disease-modifying therapies for MS regulate tight junction and adherence junction proteins in the BBB thus limiting the entry of peripheral immune cells into the central nervous system (CNS). The Epstein-Barr virus-induced gene 2 (EBI2) was shown to drive immune cell migration towards high concentration of its endogenous ligand, oxysterol 7α,25OHC, which concentrations increase during inflammation in the CNS. Here, the data showed upregulated transcripts of EBI2 and CH25H, the first enzyme in 7α, 25OHC synthesis pathway, in MS brain lesions. In vitro, cerebrospinal fluid (CSF) from patients with MS downregulated HSD3B7, the 7α, 25OHC degrading enzyme, and VE-cadherin levels in the tri-cell human BBB spheroid model. Importantly, EBI2 signalling mediated the attachment of MS patient-derived CD4+ T cells to the BBB spheroids. The data raises the possibility that elevated oxysterol levels in an inflamed brain might trigger a downregulation of VE-cadherin in endothelial cells, potentially easing the CNS infiltration of EBI2-expressing immune cells. This process can be modulated through the use of EBI2 ligands, suggesting a potential pathway for therapeutic intervention. |
| format | Article |
| id | doaj-art-cc43b7f03ee74fecb2cee51641d9c810 |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-cc43b7f03ee74fecb2cee51641d9c8102025-08-20T03:31:34ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-08-014710104510.1016/j.bbih.2025.101045EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier modelFionä Caratis0Inez Mruk1Klaudia Konieczna-Wolska2Bartłomiej Rojek3Marek Hałas4Paulina Czaplewska5Bartosz Karaszewski6Tomomi Furihata7Aleksandra Rutkowska8Department of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, PolandLaboratory of Mass Spectrometry-Core Facility Laboratories, Intercollegiate Faculty of Biotechnology UG and MUG, University of Gdańsk, Gdańsk, PolandDepartment of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland; Tri-City Central Animal Laboratory Research and Service Center, Medical University of Gdańsk, Gdańsk, PolandDepartment of Adult Neurology, Medical University of Gdańsk and University Clinical Center, Gdańsk, PolandDepartment of Adult Neurology, Medical University of Gdańsk and University Clinical Center, Gdańsk, PolandLaboratory of Mass Spectrometry-Core Facility Laboratories, Intercollegiate Faculty of Biotechnology UG and MUG, University of Gdańsk, Gdańsk, PolandDepartment of Adult Neurology, Medical University of Gdańsk and University Clinical Center, Gdańsk, Poland; Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, PolandLaboratory of Clinical Pharmacy and Experimental Therapeutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, JapanDepartment of Anatomy and Neurobiology, Medical University of Gdańsk, Gdańsk, Poland; Corresponding author.Changes in the function of the blood-brain barrier (BBB) are one of the hallmarks of multiple sclerosis (MS) and are observed at very early stages of the disease. Several disease-modifying therapies for MS regulate tight junction and adherence junction proteins in the BBB thus limiting the entry of peripheral immune cells into the central nervous system (CNS). The Epstein-Barr virus-induced gene 2 (EBI2) was shown to drive immune cell migration towards high concentration of its endogenous ligand, oxysterol 7α,25OHC, which concentrations increase during inflammation in the CNS. Here, the data showed upregulated transcripts of EBI2 and CH25H, the first enzyme in 7α, 25OHC synthesis pathway, in MS brain lesions. In vitro, cerebrospinal fluid (CSF) from patients with MS downregulated HSD3B7, the 7α, 25OHC degrading enzyme, and VE-cadherin levels in the tri-cell human BBB spheroid model. Importantly, EBI2 signalling mediated the attachment of MS patient-derived CD4+ T cells to the BBB spheroids. The data raises the possibility that elevated oxysterol levels in an inflamed brain might trigger a downregulation of VE-cadherin in endothelial cells, potentially easing the CNS infiltration of EBI2-expressing immune cells. This process can be modulated through the use of EBI2 ligands, suggesting a potential pathway for therapeutic intervention.http://www.sciencedirect.com/science/article/pii/S2666354625001036Multiple sclerosisNeuroinflammationOxysterolsEBI2Blood-brain barrierCerebrospinal fluid |
| spellingShingle | Fionä Caratis Inez Mruk Klaudia Konieczna-Wolska Bartłomiej Rojek Marek Hałas Paulina Czaplewska Bartosz Karaszewski Tomomi Furihata Aleksandra Rutkowska EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model Brain, Behavior, & Immunity - Health Multiple sclerosis Neuroinflammation Oxysterols EBI2 Blood-brain barrier Cerebrospinal fluid |
| title | EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model |
| title_full | EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model |
| title_fullStr | EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model |
| title_full_unstemmed | EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model |
| title_short | EBI2-oxysterol signalling regulates VE-cadherin expression and multiple sclerosis CD4+ T cell attachment to a human tri-cell spheroid blood-brain barrier model |
| title_sort | ebi2 oxysterol signalling regulates ve cadherin expression and multiple sclerosis cd4 t cell attachment to a human tri cell spheroid blood brain barrier model |
| topic | Multiple sclerosis Neuroinflammation Oxysterols EBI2 Blood-brain barrier Cerebrospinal fluid |
| url | http://www.sciencedirect.com/science/article/pii/S2666354625001036 |
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