Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wolf, D; Hohmann, JD; Wiedemann, A; Bledzka, K; Blankenbach, H; Marchini, T; Gutte, K; Zeschky, K; Bassler, N; Hoppe, N; Rodriguez, AO; Herr, N; Hilgendorf, I; Stachon, P; Willecke, F; Duerschmied, D; von zur Muhlen, C; Soloviev, DA; Zhang, L; Bode, C; Plow, EF; Libby, P; Peter, K; Zirlik, A.
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.
CIRC RES. 2011; 109(11): 1269-1279.
Doi: 10.1161/CIRCRESAHA.111.247684
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Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Zirlik Andreas
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- Abstract:
- 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. 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. 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. 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Amino Acid Motifs -
- Animals -
- Atherosclerosis - genetics
- Atherosclerosis - metabolism
- Atherosclerosis - prevention & control
- Bleeding Time -
- Blood Coagulation - drug effects
- Blood Coagulation - physiology
- CD40 Ligand - metabolism
- CHO Cells -
- Cells, Cultured -
- Chemotaxis, Leukocyte - physiology
- Cricetinae -
- Humans -
- Macrophage-1 Antigen - metabolism
- Male -
- Mice -
- Mice, Inbred C57BL -
- Mice, Knockout -
- Models, Molecular -
- Peptide Fragments - pharmacology
- Peptide Fragments - therapeutic use
- Peptides, Cyclic - pharmacology
- Peritonitis - blood
- Peritonitis - prevention & control
- Protein Conformation -
- Protein Interaction Mapping -
- Protein Structure, Tertiary -
- Receptors, LDL - deficiency
- Recombinant Fusion Proteins - physiology
- Surface Plasmon Resonance -
- Thrombosis - etiology
- Find related publications in this database (Keywords)
- atherosclerosis
- inflammation
- CD40L
- Mac-1
- peptide inhibitor