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The role of EphB/ephrinB in inflammation

Liu, Hui

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The binding of membrane-associated ephrinB ligands to corresponding EphB receptors in endothelial cells (ECs) is pivotal for orchestrating the development of the circulatory system. However, only little is known about their function in adult blood vessels. In this context, we observed that the ligands ephrinB1 and ephrinB2 are localized on the surface of ECs where their expression is upregulated during inflammation, while EphB2 receptors are located on the surface of monocytes. Consequently, we hypothesized that these ligands bind to EphB receptors expressed in monocytes under pro-inflammatory conditions. To study functional consequences of their ligand-receptor interactions, ECs were exposed to EphB2 receptor bodies or EphB2-overexpressing mouse myeloma cells upon siRNA-mediated knockdown of ephrinB1 or ephrinB2. Based on this experimental setup, we analyzed the pro-inflammatory differentiation of the ECs and the transmigration of monocytes through the EC monolayer. Whereas forward signaling downstream of the EphB receptors promotes activation of monocytes, ephrinB reverse signaling induces the deposition of von Willebrand factor on the ECs surface, increases the expression of E-selectin, VCAM-1 and granulocyte-macrophage colony-stimulating factor in ECs, and consequently stimulates monocyte attachment. Moreover, ephrinB1 and ephrinB2 are crucial for the transmigration of monocytes through the endothelial cell monolayer. Their activation by EphB2 not only promotes PECAM-1 phosphorylation through a Src-dependent mechanism while diminishing SHP-2 activity, but also triggers displacement of VE-cadherin from interendothelial cell junctions. In addition, EphB2 stimulation increases the permeability of endothelial cells. In vivo, endothelial cell specific ephrinB2 ablation was induced by injecting tamoxifen in Tie2-CreERT2/ephrinB2flox/flox mice. Three distinct types of inflammatory models-TPA-induced ear edema, thioglycollate-elicited peritonitis, atherosclerosis, as well as an arteriogenesis model were employed to analyze the impact of ephrinB2 on monocyte extravasation and progression of pathological processes. However, all four models indicated that loss of endothelial ephrinB2 has no impact on monocyte infiltration, inflammatory pathology, and progression of arteriogenesis. This might be due to the limitations of the utilized models and compensatory effects of ephrinB1. Collectively, our data indicates for the first time that the EphB/ephrinB system contributes to inflammatory responses of ECs whereby ephrinB reverse signaling supports adhesion and transmigration of EphB2-expressing monocytes, and increases endothelial cell permeability.

Item Type: Dissertation
Supervisor: Hecker, Prof. Dr. Markus
Place of Publication: Heidelberg, Germany
Date of thesis defense: 18 November 2013
Date Deposited: 02 Dec 2013 07:05
Date: 2013
Faculties / Institutes: Medizinische Fakultät Heidelberg > Institut fuer Physiologie und Pathophysiologie
Subjects: 570 Life sciences
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