dc.creator | Wolf, Dennis | |
dc.creator | Hohmann, Jan David | |
dc.creator | Wiedemann, Ansgar | |
dc.creator | Bledzka, Kamila | |
dc.creator | Blankenbach, Hermann | |
dc.creator | Marchini, Timoteo Oscar | |
dc.creator | Gutte, Katharina | |
dc.creator | Zeschky, Katharina | |
dc.creator | Bassler, Nicole | |
dc.creator | Hoppe, Natalie | |
dc.creator | Rodriguez, Alexandra Ortiz | |
dc.creator | Herr, Nadine | |
dc.creator | Hilgendorf, Ingo | |
dc.creator | Stachon, Peter | |
dc.creator | Willecke, Florian | |
dc.creator | Duerschmied, Daniel | |
dc.creator | von zur Muhlen, Constantin | |
dc.creator | Soloviev, Dmitry A. | |
dc.creator | Zhang, Li | |
dc.creator | Bode, Christoph | |
dc.creator | Plow, Edward F. | |
dc.creator | Libby, Peter | |
dc.creator | Peter, Karlheinz | |
dc.creator | Zirlik, Andreas | |
dc.date.accessioned | 2019-01-09T18:31:16Z | |
dc.date.accessioned | 2022-10-15T06:20:36Z | |
dc.date.available | 2019-01-09T18:31:16Z | |
dc.date.available | 2022-10-15T06:20:36Z | |
dc.date.created | 2019-01-09T18:31:16Z | |
dc.date.issued | 2011-11 | |
dc.identifier | 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 | |
dc.identifier | 0009-7330 | |
dc.identifier | http://hdl.handle.net/11336/67807 | |
dc.identifier | CONICET Digital | |
dc.identifier | CONICET | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/4354615 | |
dc.description.abstract | 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. | |
dc.language | eng | |
dc.publisher | American Heart Association | |
dc.relation | info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1161/CIRCRESAHA.111.247684 | |
dc.relation | info:eu-repo/semantics/altIdentifier/url/https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.111.247684 | |
dc.rights | https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | Atherosclerosis | |
dc.subject | Cd40l | |
dc.subject | Inflammation | |
dc.subject | Mac-1 | |
dc.subject | Peptide Inhibitor | |
dc.title | 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 | |
dc.type | info:eu-repo/semantics/article | |
dc.type | info:ar-repo/semantics/artículo | |
dc.type | info:eu-repo/semantics/publishedVersion | |