Intercellular Interactomics of Human Brain Endothelial Cells and Th17 Lymphocytes: A Novel Strategy for Identifying Therapeutic Targets of CNS Inflammation
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. 1. Leukocyte Infiltration in CNS Disorders The central nervous system (CNS) has long been regarded as an “immune privileged” organ, being both immunologically inert and immunologically separated from the peripheral immune system [1]. Current data, however, indicates that the CNS is both immune competent and actively interactive with the peripheral immune system [2]. In physiological conditions, a limited number of peripheral immune cells cross the blood-brain barrier (BBB) and enter the CNS in a process called “immune surveillance” [1]. Many neurological diseases are associated with a much higher rate of leukocyte trafficking into the CNS, resulting in leukocyte infiltration and leukocyte-mediated neuronal damage. CNS inflammation is a major contributor to the diverse forms of brain injury seen in cerebral ischemia, multiple sclerosis, cerebral infection, and epilepsy [3–5]. A growing body of recent evidence shows that infiltration of a subset of IL-17-producing T-lymphocytes into the CNS contributes to the pathogenesis of multiple sclerosis, and cerebral ischemia. In multiple sclerosis these cells are CD4+ T helper 17 (Th17) lymphocytes that have CNS-homing properties and
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