Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 86, Issue 4, Pages 903-911Publisher
WILEY
DOI: 10.1189/jlb.0308158
Keywords
chemokine; chemotaxis; monocyte; adhesion; migration
Categories
Funding
- Association pour la Recherche sur le Cancer (ARC)
- Institut du Cancer (InCa)
- European FP6 contracts INNOCHEM [LSHB-CT-2005518167]
- ATTACK [LSHC-CT-2005-018914]
- Swiss National Science Foundation [3100A0-110042]
- Assistance Publique-Hopitaux de Paris-Institut Pasteur
- Assistance Publique-Hopitaux de Paris
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Chemokines are mainly involved in the recruitment of leukocytes into tissues, a key feature of inflammation. Through its unique receptor CX3CR1, the chemokine CX3CL1 participates in diverse inflammatory processes including arterial atherosclerosis and cerebral or renal inflammation. Using a phage display strategy, we engineered a hCX3CL1 analog (named F1) with a modified N terminus. F1 bound specifically to cells expressing hCX3CR1 and had a K-d value close to that of native CX3CL1. F1 was not a signaling molecule and did not induce chemotaxis, calcium flux, or CX3CR1 internalization. However, it potently inhibited the CX3CL1-induced calcium flux and chemotaxis in CX3CR1-expressing primary cells of human and murine origin with an IC50 of 5-50 nM. It also efficiently inhibited the cell adhesion mediated by the CX3CL1-CX3CR1 axis. Finally, in a noninfectious murine model of peritonitis, F1 strongly inhibited macrophage accumulation. These data reveal a prototype molecule that is the first bona fide antagonist of hCX3CR1. This molecule could be used as a lead compound for the development of a novel class of anti-inflammatory substances that act by inhibiting CX3CR1. J. Leukoc. Biol. 86: 903-911; 2009.
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