An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Identification of a chemokine analogue that antagonized CX3CL1‐CX3CR1‐dependent responses both in vitro and in vivo 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 di...

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Published in:	Journal of leukocyte biology Vol. 86; no. 4; pp. 903 - 911
Main Authors:	Dorgham, Karim, Ghadiri, Ata, Hermand, Patricia, Rodero, Mathieu, Poupel, Lucie, Iga, Mutsumori, Hartley, Oliver, Gorochov, Guy, Combadière, Christophe, Deterre, Philippe
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-10-2009
Subjects:	adhesion Animals Anti-Inflammatory Agents, Non-Steroidal - pharmacology Calcium - metabolism Cell Adhesion - drug effects chemokine Chemokine CX3CL1 - metabolism chemotaxis Chemotaxis - drug effects CHO Cells Cricetinae Cricetulus CX3C Chemokine Receptor 1 Disease Models, Animal Dose-Response Relationship, Drug Humans Inflammation - drug therapy Inflammation - metabolism Life Sciences Macrophages, Peritoneal - metabolism Mice migration monocyte Peptides - pharmacology Peritonitis - drug therapy Peritonitis - metabolism Receptors, Chemokine - antagonists & inhibitors Receptors, Chemokine - metabolism
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Summary:	Identification of a chemokine analogue that antagonized CX3CL1‐CX3CR1‐dependent responses both in vitro and in vivo 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 Kd 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.0308158