Leukocyte activation and adhesion to the endothelium are pivotal steps in the recruitment of cells to the inflamed tissue. This coordinated sequence of adhesive events on the endothelium includes the rolling, the leukocyte activation, the firm adhesion to and subsequent locomotion and the trans-endothelial migration. During trans-endothelial migration, molecules located at the interendothelial junctions may facilitate the passage of the transmigrating leukocyte. We have recently identified the third member of the JAM family, junctional adhesion molecule-C (JAM-C), and could demonstrate that JAM-C is expressed at the interendothelial junctions and serves as a counter-receptor for neutrophil Mac-1, mediating the transendothelial migration of the neutrophils in vitro and in vivo. In contrast, JAM-C does not participate in the adhesion of leukocytes to quiescent endothelial cells, as it is located at the interendothelial junctions and is not available for leukocyte integrin Mac-1. In contrast to quiescent endothelial cells, where JAM-C localized strictly to cell-cell contacts and colocalized with a tight junction component, ZO-1, JAM-C localization on oxLDL stimulated endothelial cells was no more restricted to intercellular contacts. In particular, on oxLDL-pretreated HUVEC a part of JAM-C re-distributed to sites distinct of the interendothelial contacts (at the apical surface). In this case JAM-C on endothelial cells may also function to mediate Mac-1-dependent adhesion of leukocytes. Thus, JAM-C participates in the oxLDL-mediated upregulation of leukocyte extravasation with potential implications for the enhanced inflammatory cell recruitment to the atherosclerotic vessel wall. In addition, to the heterophilic interaction of JAM-C with Mac-1, we also identified JAM-C to interact homophilically. We could characterize the biochemical properties of this interaction. Through the homophilic interaction of JAM-C, lung carcinoma cells adhered to endothelial cells.
The aim of our current studies is:a) The role of JAM-C in endothelial paracellular permeability. As JAM-C is loacated at the interendothelial tight junctions, it may regulate permeability of the monolayer, and permeability changes are crucial during inflammatory reactions and in angiogenesis. JAM-C is recruited to the junctions by vasoactive substances to regulate permeability. JAM-C regulates the activity of small GTPases and thereby the adhesiveness of adherens junctions. Moreover, JAM-C in endothelial cells facilitates stress fiber formation. JAM-C inhibition in vivo blocks the VEGF or histamine induced permeability as well as hypoxia-driven retina angiogenesis. The role of JAM-C in these processes will be investigated in detail with the JAM-C ko mice.b) By regulating VE-cadherin-mediated adherens junctions and vascular endothelial permeability JAM-C also modulates neutrophil and T cell transendothelial migration. Here, we need to understand how JAM-C is distributed in the interendothelial contacts during leukocyte transmigration?In addition, the importance of JAM-C in leukocyte transendothelial migration in vivo will be tested with the use of JAM-C -/- mice, by using several inflammation models, such as lung inflammation and experimental autoimmune encephalomyelitis.c) The homophilic interaction of JAM-C mediates tumor cell adhesion to the endothelium. By using the JAM-C ko mice, tumor (specifically melanoma) metastasis will be studied.
