Charakterisierung alternativer LFA-1 Liganden bei entzündlicher und atherogener Zellrekrutierung
Final Report Abstract
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.
Publications
- LFA-1 binding destabilizes the JAM-A 29mmune29ng29 interaction during leukocyte transmigration. Biophys. J. 2009;96:285-293
Wojcikiewicz EP, Koenen RR, Fraemohs L, Minkiewicz J, Azad H, Weber C, Moy VT
(See online at https://doi.org/10.1529/biophysj.108.135491) - Regulated release and functional modulation of Junctional Adhesion Molecule A by disintegrin metalloproteinases. Blood. 2009;113:4799-4809
Koenen RR, Pruessmeyer J, Soehnlein O, Fraemohs L, Zernecke A, Schwarz N, Reiss K, Sarabi A, Lindbom L, Hackeng TM, Weber C, Ludwig A
(See online at https://doi.org/10.1182/blood-2008-04-152330) - Platelets and platelet-derived microparticles in vascular inflammatory disease. Inflamm. Allergy Drug Targets. 2010;9:346-354
Vasina E, Heemskerk JW, Weber C, Koenen RR
(See online at https://doi.org/10.2174/187152810793938008) - Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis. 2011;2:e211
Vasina EM, Cauwenberghs S, Feijge MA, Heemskerk JW, Weber C, Koenen RR
(See online at https://doi.org/10.1038/cddis.2011.94) - Platelets: Key players in vascular inflammation. J. Leukoc. Biol. 2012;92:1167-1175
Projahn D, Koenen RR
(See online at https://doi.org/10.1189/jlb.0312151) - 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
- Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial Junctional Adhesion Molecule-A redistribution. Atherosclerosis. 2014;234:254-264
Schmitt MM, Fraemohs L, Hackeng TM, Weber C, Koenen RR
(See online at https://doi.org/10.1016/j.atherosclerosis.2014.03.014) - 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 PV, Gijbels MJ, Habbeddine M, Cudejko C, Asare Y, Theelen W, Zhou B, Doring Y, Drechsler M, Pawig L, Simsekyilmaz S, Koenen RR, de Winther MP, Lawrence T, Bernhagen J, Zernecke A, Weber C, Noels H
(See online at https://doi.org/10.1371/journal.pone.0087452) - 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 D, Simsekyilmaz S, Singh S, Kanzler I, Kramp BK, Langer M, Burlacu A, Bernhagen J, Klee D, Zernecke A, Hackeng TM, Groll J, Weber C, Liehn EA, Koenen RR
(See online at https://doi.org/10.1111/jcmm.12225) - Endothelial Junctional Adhesion Molecule- A guides monocytes into flow-dependent predilection sites of atherosclerosis. Circulation. 2014;129:66-76
Schmitt MM, Megens RT, Zernecke A, Bidzhekov K, van den Akker NM, Rademakers T, van Zandvoort MA, Hackeng TM, Koenen RR, Weber C
(See online at https://doi.org/10.1161/CIRCULATIONAHA.113.004149) - TNF-α and IFN-γ promote lymphocyte adhesion to endo-thelial junctional regions facilitating transendothelial migration. J. Leukoc. Biol. 2014;95:265-274
Jaczewska J, Abdulreda MH, Yau CY, Schmitt MM, Schubert I, Berggren PO, Weber C, Koenen RR, Moy VT, Wojcikiewicz EP
(See online at https://doi.org/10.1189/jlb.0412205) - Hyperreactivity of Junctional Adhesion Molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice. Circ. Res. 2015;116:587-599
Karshovska E, Zhao Z, Blanchet X, Schmitt MM, Bidzhekov K, Soehnlein O, von Hundelshausen P, Mattheij NJ, Cosemans JM, Megens RT, Koeppel TA, Schober A, Hackeng TM, Weber C, Koenen RR
(See online at https://doi.org/10.1161/CIRCRESAHA.116.304035) - Microvesicles from platelets: Novel drivers of vascular inflammation. Thromb. Haemost. 2015;114:228-236
Vajen T, Mause SF, Koenen RR
(See online at https://doi.org/10.1160/TH14-11-0962)
