Charakterisierung alternativer LFA-1 Liganden bei entzündlicher und atherogener Zellrekrutierung

• Antragsteller: Professor Rory R. Koenen, Ph.D.
• Fachliche Zuordnung: Kardiologie, Angiologie
• Förderung: Förderung von 2007 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 29385330

• Erstellungsjahr: 2015

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)

• 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
  
• 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
  
• 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
  
• 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
  
• Platelets: Key players in vascular inflammation. J. Leukoc. Biol. 2012;92:1167-1175
  Projahn D, Koenen RR
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• Microvesicles from platelets: Novel drivers of vascular inflammation. Thromb. Haemost. 2015;114:228-236
  Vajen T, Mause SF, Koenen RR