Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0308158

Received for publication March 4, 2008.
Revised May 6, 2009.
Accepted for publication May 7, 2009.

Article

An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Karim Dorgham *, Ata Ghadiri *, Patricia Hermand *, Mathieu Rodero *, Lucie Poupel {dagger}, Mutsumori Iga *, Oliver Hartley {ddagger}, Guy Gorochov *{dagger}, Christophe Combadière *{dagger}, and Philippe Deterre *@

*INSERM UMR-S 945 and UPMC Univ Paris 06, Faculté de Médecine Pitié-Salpêtrière, Laboratoire Immunité et Infection, Paris, France;{ddagger}Département de Biologie Structurale et de Bioinformatique, Centre Médical Universitaire, Geneva, Switzerland; and{dagger}AP-HP Pitié-Salpêtrière, Laboratoire d’Immunologie Cellulaire, Paris, France

@ To whom correspondence should be addressed. E-mail: philippe.deterre{at}upmc.fr.


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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.

Key Words: chemokine • chemotaxis • monocyte • adhesion • migration