An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Dorgham, Karim, Ghadiri, Ata, Hermand, Patricia, Rodero, Mathieu, Poupel, Lucie, Iga, Mutsumori, Hartley, Oliver, Gorochov, Guy, Combadière, Christophe and Deterre, Philippe (2009) An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. Journal of Leukocyte Biology, 86 4: 903-911. doi:10.1189/jlb.0308158

Author Dorgham, Karim
Ghadiri, Ata
Hermand, Patricia
Rodero, Mathieu
Poupel, Lucie
Iga, Mutsumori
Hartley, Oliver
Gorochov, Guy
Combadière, Christophe
Deterre, Philippe
Title An engineered CX3CR1 antagonist endowed with anti-inflammatory activity
Journal name Journal of Leukocyte Biology   Check publisher's open access policy
ISSN 0741-5400
Publication date 2009-10
Sub-type Article (original research)
DOI 10.1189/jlb.0308158
Volume 86
Issue 4
Start page 903
End page 911
Total pages 9
Place of publication Bethesda, Md., U. S. A.
Publisher Federation of American Societies for Experimental Biology
Language eng
Subject 1107 Immunology
Abstract 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.
Keyword Adhesion
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Centre for Clinical Research Publications
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Created: Wed, 29 Sep 2010, 11:15:00 EST by Ms May Balasaize on behalf of Faculty Of Health Sciences