Intercellular interactomics of human brain endothelial cells and th17 lymphocytes: a novel strategy for identifying therapeutic targets of CNS inflammation.

Abstract

Leukocyte infiltration across an activated brain endothelium contributes to the neuroinflammation seen in many neurological disorders. Recent evidence shows that IL-17-producing T-lymphocytes (e.g., Th17 cells) possess brain-homing capability and contribute to the pathogenesis of multiple sclerosis and cerebral ischemia. The leukocyte transmigration across the endothelium is a highly regulated, multistep process involving intercellular communications and interactions between the leukocytes and endothelial cells. The molecules involved in the process are attractive therapeutic targets for inhibiting leukocyte brain migration. We hypothesized and have been successful in demonstrating that molecules of potential therapeutic significance involved in Th17-brain endothelial cell (BEC) communications and interactions can be discovered through the combination of advanced membrane/submembrane proteomic and interactomic methods. We describe elements of this strategy and preliminary results obtained in method and approach development. The Th17-BEC interaction network provides new insights into the complexity of the transmigration process mediated by well-organized, subcellularly localized molecular interactions. These molecules and interactions are potential diagnostic, therapeutic, or theranostic targets for treatment of neurological conditions accompanied or caused by leukocyte infiltration.