info:eu-repo/semantics/article
Binding of CD40L to Mac-1's i-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis-but does not affect immunity and thrombosis in mice
Fecha
2011-11Registro en:
Wolf, Dennis; Hohmann, Jan David; Wiedemann, Ansgar; Bledzka, Kamila; Blankenbach, Hermann; et al.; Binding of CD40L to Mac-1's i-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis-but does not affect immunity and thrombosis in mice; American Heart Association; Circulation Research; 109; 11; 11-2011; 1269-1279
0009-7330
CONICET Digital
CONICET
Autor
Wolf, Dennis
Hohmann, Jan David
Wiedemann, Ansgar
Bledzka, Kamila
Blankenbach, Hermann
Marchini, Timoteo Oscar
Gutte, Katharina
Zeschky, Katharina
Bassler, Nicole
Hoppe, Natalie
Rodriguez, Alexandra Ortiz
Herr, Nadine
Hilgendorf, Ingo
Stachon, Peter
Willecke, Florian
Duerschmied, Daniel
von zur Muhlen, Constantin
Soloviev, Dmitry A.
Zhang, Li
Bode, Christoph
Plow, Edward F.
Libby, Peter
Peter, Karlheinz
Zirlik, Andreas
Resumen
Rationale: CD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since CD40L potently regulates immune function and hemostasis by interaction with CD40 receptor and the platelet integrin GPIIb/IIIa, its global inhibition compromises host defense and generated thromboembolic complications in clinical trials. We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor. Objective: Here, we molecularly characterized the CD40L-Mac-1 interaction and tested whether its selective inhibition by a small peptide modulates inflammation and atherogenesis in vivo. Methods and Results: CD40L concentration-dependently bound to Mac-1 I-domain in solid phase binding assays, and a high-affinity interaction was revealed by surface-plasmon-resonance analysis. We identified the motif EQLKKSKTL, an exposed loop between the α1 helix and the β-sheet B, on Mac-1 as binding site for CD40L. A linear peptide mimicking this sequence, M7, specifically inhibited the interaction of CD40L and Mac-1. A cyclisized version optimized for in vivo use, cM7, decreased peritoneal inflammation and inflammatory cell recruitment in vivo. Finally, LDLr -/- mice treated with intraperitoneal injections of cM7 developed smaller, less inflamed atherosclerotic lesions featuring characteristics of stability. However, cM7 did not interfere with CD40L-CD40 binding in vitro and CD40L-GPIIb/IIIa-mediated thrombus formation in vivo. Conclusions: We present the novel finding that CD40L binds to the EQLKKSKTL motif on Mac-1 mediating leukocyte recruitment and atherogenesis. Specific inhibition of CD40L-Mac-1 binding may represent an attractive anti-inflammatory treatment strategy for atherosclerosis and other inflammatory conditions, potentially avoiding the unwanted immunologic and thrombotic effects of global inhibition of CD40L.