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

• DOI: 10.1161/circresaha.111.247684
• Publication Date: 2011-10-14T04:47:29Z
• Authors: Dennis Wolf; Jan-David Hohmann; Ansgar Wiedemann; Kamila Bledzka; Hermann Blankenbach; Timoteo Marchini; Katharina Gutte; Katharina Zeschky; Nicole Bassler; Natalie Hoppe; Alexandra Ortiz R...; Nadine Herr; Ingo Hilgendorf; Peter Stachon; Florian Willecke; Daniel Duerschmied; Constantin von zu...; Dmitry A. Soloviev; Li Zhang; Christoph Bode; Edward F. Plow; Peter Libby; Karlheinz Peter; Andreas Zirlik
• Keywords: CD47; RGD motif

Rationale: CD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since potently regulates immune function and hemostasis by interaction with CD40 receptor the platelet integrin GPIIb/IIIa, its global inhibition compromises host defense generated thromboembolic complications clinical trials. We recently reported that mediates atherogenesis independently of proposed Mac-1 an alternate receptor. Objective: Here, we molecularly characterized CD40L-Mac-1 tested whether selective a small peptide modulates inflammation vivo. Methods Results: concentration-dependently bound to I-domain solid phase binding assays, high-affinity was revealed surface-plasmon-resonance analysis. identified motif EQLKKSKTL, exposed loop between α1 helix β-sheet B, on site for CD40L. A linear mimicking this sequence, M7, specifically inhibited Mac-1. cyclisized version optimized vivo use, cM7, decreased peritoneal cell recruitment Finally, LDLr −/− mice treated intraperitoneal injections cM7 developed smaller, less inflamed atherosclerotic lesions featuring characteristics stability. did not interfere CD40L-CD40 vitro CD40L-GPIIb/IIIa-mediated thrombus formation Conclusions: present novel finding binds EQLKKSKTL mediating leukocyte atherogenesis. Specific may represent attractive anti-inflammatory treatment strategy atherosclerosis other conditions, potentially avoiding unwanted immunologic thrombotic effects