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

被引：98

作者：

Wolf, Dennis ^{[1
,2
]}

Hohmann, Jan-David ^{[1
]}

Wiedemann, Ansgar ^{[2
]}

Bledzka, Kamila ^{[3
]}

Blankenbach, Hermann ^{[2
]}

Marchini, Timoteo ^{[2
]}

Gutte, Katharina ^{[2
]}

Zeschky, Katharina ^{[2
]}

Bassler, Nicole ^{[1
]}

Hoppe, Natalie ^{[2
]}

Rodriguez, Alexandra Ortiz ^{[2
]}

Herr, Nadine ^{[2
]}

Hilgendorf, Ingo ^{[2
]}

Stachon, Peter ^{[2
]}

Willecke, Florian ^{[2
]}

Duerschmied, Daniel ^{[2
]}

von zur Muhlen, Constantin ^{[2
]}

Soloviev, Dmitry A. ^{[3
]}

Zhang, Li ^{[4
]}

Bode, Christoph ^{[2
]}

Plow, Edward F. ^{[3
]}

Libby, Peter ^{[5
]}

Peter, Karlheinz ^{[1
]}

Zirlik, Andreas ^{[2
]}

机构：

[1] Baker IDI Heart & Diabet Inst, Melbourne, Vic 8008, Australia

[2] Univ Freiburg, Dept Cardiol, Atherogenesis Res Grp, Freiburg, Germany

[3] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

[4] Univ Maryland, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA

来源：

CIRCULATION RESEARCH | 2011年 / 109卷 / 11期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

atherosclerosis; inflammation; CD40L; Mac-1; peptide inhibitor; INTERCELLULAR-ADHESION MOLECULE-1; INFLAMMATORY CELL RECRUITMENT; NEUTROPHIL INHIBITORY FACTOR; ALPHA-INDUCED INFLAMMATION; INTEGRIN ALPHA(M)BETA(2); ACTIVATED PLATELETS; ENDOTHELIAL-CELLS; RECOGNITION SITE; LIGAND-BINDING; CD11B/CD18;

D O I：

10.1161/CIRCRESAHA.111.247684

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 alpha 1 helix and the beta-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. (Circ Res. 2011; 109: 1269-1279.)

引用

页码：1269 / U202

页数：32

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