Investigating the role of the EFNA4-EphA2 interaction on blood-brain barrier integrity in the context of Multiple Sclerosis

Details

Supervisors

Van Pesch, Vincent

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enMultiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation and demyelination of the central nervous system (CNS), as well as a disruption of the blood-brain barrier (BBB). B lymphocytes play an important role in the inflammatory cascade leading to CNS damage. Eph receptors and their ligands, ephrins, play important roles in neurodevelopment and have been extensively studied in the context of cancer. However, their involvement in neuroinflammation remains poorly understood, despite multiple studies suggesting that they may play important roles. Previous studies have highlighted the impact of EphA2 receptor stimulation by EFNA1 on tight junction integrity and BBB breakdown. However, the role of EFNA4 on BBB integrity has not yet been investigated. We recently identified an EFNA4-expressing B cell subpopulation suggesting that EFNA4 may also be relevant in the context of MS. This project aims to investigate the role of the EFNA4-EphA2 interaction in BBB disruption in the context of increased MS-related inflammation. Using the human brain endothelial cell line hCMEC/D3 as a BBB model, we assessed EphA2 expression and endothelial cell responses following stimulation with different pro- and anti-inflammatory cytokines. Our results show that EphA2 expression is upregulated, at both the mRNA and protein levels, in response to a proinflammatory combination of TNF𝛼 and IFN𝛾, which is relevant to MS pathology. Tight junction mRNA expression was evaluated following EphA2 stimulation with recombinant EFNA4; however, no detectable effects were observed. At the protein level, EphA2 activation seems to decrease occludin expression, although no changes seem to occur in TEER measurements. A better understanding of the EFNA4-EphA2 interaction may reveal novel pathways involved in BBB disruption in MS, which could contribute to new therapeutic strategies to limit neuroinflammation and disease progression.