Charakterisierung alternativer LFA-1 Liganden bei entzündlicher und atherogener Zellrekrutierung
Zusammenfassung der Projektergebnisse
In this project, we focused on the cell-specific roles of Junctional Adhesion Molecule A (JAM-A) in vascular inflammation and remodeling. Using state-of-the-art microscopy techniques, e.g. atomic force and 2-photon laser scanning microscopy, we could further establish and characterize the important role of endothelial JAM-A in the recruitment of leukocytes. First, we showed that binding of the leukocyte integrin LFA-1 to JAM-A led to a destabilization of the 34mmune34ng34 interaction of JAM-A, a process that has implications for transendothelial migration. During inflammation, JAM-A is both redistributed and proteolytically released from the cell membrane and these processes can subsequently affect leukocyte recruitment to the vascular endothelium. In a relevant mouse model of diet-induced atherosclerosis, the pathophysiologic relevance of endothelial cell- and bone marrow-derived JAM-A was established. Whereas deletion of JAM-A in leukocytes led to an increase of plaque formation, downregulation of endothelial JAM-A resulted in a reduction of atherosclerosis. Multiphoton microscopy revealed a disordered endothelial distribution of JAM-A at sites of plaque development in hyperlipidemic mice, which might facilitate atherogenic monocyte recruitment. Thus, endothelial JAM-A might serve as a molecular beacon guiding leukocytes to sites of developing atherosclerosis. Finally, we have further characterized the role of JAM-A in platelet signaling and confirmed that JAM-A–deficiency in platelets was accompanied by hyperreactivity. As a consequence, JAM-A–deficient platelets appeared to release more chemokines and more avidly interacted with leukocytes and endothelial cells. During the course of a highfat diet, the platelet hyperreactivity in the absence of JAM-A accelerated the development of atherosclerotic plaques in mice. Taken together, the results from this project highlight the versatile and cell-specific roles of JAM-A in the recruitment of leukocytes that drives the development of atherosclerosis.
Projektbezogene Publikationen (Auswahl)
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LFA-1 binding destabilizes the JAM-A 29mmune29ng29 interaction during leukocyte transmigration. Biophys. J. 2009;96:285-293
Wojcikiewicz, Ewa P.; Koenen, Rory R.; Fraemohs, Line; Minkiewicz, Julia; Azad, Hashem; Weber, Christian & Moy, Vincent T.
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Regulated release and functional modulation of Junctional Adhesion Molecule A by disintegrin metalloproteinases. Blood. 2009;113:4799-4809
Koenen, Rory R.; Pruessmeyer, Jessica; Soehnlein, Oliver; Fraemohs, Line; Zernecke, Alma; Schwarz, Nicole; Reiss, Karina; Sarabi, Alisina; Lindbom, Lennart; Hackeng, Tilman M.; Weber, Christian & Ludwig, Andreas
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Platelets and platelet-derived microparticles in vascular inflammatory disease. Inflamm. Allergy Drug Targets. 2010;9:346-354
Vasina, Elena; W.M. Heemskerk, Johan; Weber, Christian & R. Koenen, Rory
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Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis. 2011;2:e211
Vasina, E. M.; Cauwenberghs, S.; Feijge, M. A. H.; Heemskerk, J. W. M.; Weber, C. & Koenen, R. R.
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Platelets: Key players in vascular inflammation. J. Leukoc. Biol. 2012;92:1167-1175
Projahn, Delia & Koenen, Rory R.
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Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. Am. J. Blood Res. 2013;3:107-123
Vasina EM, Cauwenberghs S, Staudt M, Feijge MA, Weber C, Koenen RR, Heemskerk JW
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TNF-α and IFN-γ promote lymphocyte adhesion to endo-thelial junctional regions facilitating transendothelial migration. J. Leukoc. Biol. 2014;95:265-274
Jaczewska, Justyna; Abdulreda, Midhat H.; Yau, Chi Y.; Schmitt, Martin M.; Schubert, Irene; Berggren, Per-Olof; Weber, Christian; Koenen, Rory R.; Moy, Vincent T. & Wojcikiewicz, Ewa P.
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Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial Junctional Adhesion Molecule-A redistribution. Atherosclerosis. 2014;234:254-264
Schmitt, Martin M.N.; Fraemohs, Line; Hackeng, Tilman M.; Weber, Christian & Koenen, Rory R.
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Bone marrow-specific knock-in of a non-activatable IKKalpha kinase mutant influences haematopoiesis but not atherosclerosis in apoe-deficient mice. PloS ONE. 2014;9:e87452
Tilstam, Pathricia V.; Gijbels, Marion J.; Habbeddine, Mohamed; Cudejko, Céline; Asare, Yaw; Theelen, Wendy; Zhou, Baixue; Döring, Yvonne; Drechsler, Maik; Pawig, Lukas; Simsekyilmaz, Sakine; Koenen, Rory R.; de Winther, Menno P. J.; Lawrence, Toby; Bernhagen, Jürgen; Zernecke, Alma; Weber, Christian & Noels, Heidi
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Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction. J. Cell. Mol. Med. 2014;18:790-800
Projahn, Delia; Simsekyilmaz, Sakine; Singh, Smriti; Kanzler, Isabella; Kramp, Birgit K.; Langer, Marcella; Burlacu, Alexandrina; Bernhagen, Jürgen; Klee, Doris; Zernecke, Alma; Hackeng, Tilman M.; Groll, Jürgen; Weber, Christian; Liehn, Elisa A. & Koenen, Rory R.
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Endothelial Junctional Adhesion Molecule- A guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation. 2014;129:66-76
Schmitt, Martin M.N.; Megens, Remco T.A.; Zernecke, Alma; Bidzhekov, Kiril; van den Akker, Nynke M.; Rademakers, Timo; van Zandvoort, Marc A.; Hackeng, Tilman M.; Koenen, Rory R. & Weber, Christian
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Hyperreactivity of Junctional Adhesion Molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ. Res. 2015;116:587-599
Karshovska, Ela; Zhao, Zhen; Blanchet, Xavier; Schmitt, Martin M.N.; Bidzhekov, Kiril; Soehnlein, Oliver; von Hundelshausen, Philipp; Mattheij, Nadine J.; Cosemans, Judith M.E.M.; Megens, Remco T.A.; Koeppel, Thomas A.; Schober, Andreas; Hackeng, Tilman M.; Weber, Christian & Koenen, Rory R.
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Microvesicles from platelets: Novel drivers of vascular inflammation. Thromb. Haemost. 2015;114:228-236
Vajen, Tanja; Mause, Sebastian & Koenen, Rory
