The publication detail shows the title, authors (with indicators showing other profiled authors), information on the publishing organization, abstract and a link to the article in PubMed. This abstract is what is used to create the fingerprint of the publication. If any grants are referenced by the publication, they will be listed here as well.
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.
Dennis Wolf; Jan-David Hohmann; Ansgar Wiedemann; Kamila Bledzka; Hermann Blankenbach; Timoteo Marchini; Katharina Gutte; Katharina Zeschky; Nicole Bassler; Natalie Hoppe; et al. (Profiled Author: Li Zhang)
Atherogenesis Research Group, Department of Cardiology, University of Freiburg, Germany.
Circulation research 2011;109(11):1269-79.
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.
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Sergiy Yakovlev; Li Zhang; Tatiana Ugarova; Leonid Medved
Interaction of fibrin(ogen) with leukocyte receptor alpha M beta 2 (Mac-1): further characterization and identification of a novel binding region within the central domain of the fibrinogen gamma-module.Biochemistry 2005;44(2):617-26.
Jose Ruiz; Diana Kouiavskaia; Molly Migliorini; Susan Robinson; Evgueni L Saenko; Natalia Gorlatova; Donghua Li; Daniel Lawrence; Bradley T Hyman; Karl H Weisgraber; et al.Journal of lipid research 2005;46(8):1721-31.
R Spoelgen; K W Adams; M Koker; A V Thomas; O M Andersen; P J Hallett; K K Bercury; D F Joyner; M Deng; W H Stoothoff; et al.Neuroscience 2009;158(4):1460-8.
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