Delta-Like Ligand 4 (DLL4)/Notch axis regulates EAE development by modulating T cell trafficking across the blood brain barrier

Abstract

Abstract The Notch receptor system has been suggested to play a critical role in the regulation of chemokine receptor expression on encephalitogenic T cells and subsequent T cell trafficking to the central nervous system (CNS). Here we tested whether Delta-Like Ligand (DLL) 4 (DLL4)/Notch axis regulates EAE development by modulating T effector cell trafficking mechanisms across the blood-brain barrier (BBB). Primary cultures of brain microvessel endothelial cells were established and migration of splenocytes was tested in the presence of DLL4 blocking antibody. Our data show that anti DLL4 blocks transendothelial migration of non-activated T cells, but does not influence the migration of anti CD28 and CD3-activated splenocytes. Additionally, activation of brain microvessel endothelial cells with TNFα abrogated the blocking effect of anti DLL4 in transendothelial migration of T cells. We also demonstrate that blockade of DLL4 function inhibits the development of a progressive model of clinical experimental autoimmune encephalomyelitis (EAE), in C57Bl6 mice. Based on these results, we propose that endothelial DLL4 engagement with Notch expressing T cells is critical in strengthening the neuroinflammation and blockage of DLL4 could provide novel therapies in early phases of CNS neuroinflammatory diseases.