An engineered CX3CR1 antagonist endowed with anti-inflammatory activity.
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 IC(50) 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.
Dorgham
Karim
K
INSERM UMR-S 945, UPMC Paris 6, Faculté de Médecine Pitié-Salpêtrière, Laboratoire Immunitét Infection, 75013 Paris, France.
Ghadiri
Ata
A
Hermand
Patricia
P
Rodero
Mathieu
M
Poupel
Lucie
L
Iga
Mutsumori
M
Hartley
Oliver
O
Gorochov
Guy
G
Combadière
Christophe
C
Deterre
Philippe
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016466:CHO Cells; D000073883:CX3C Chemokine Receptor 1; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D054428:Chemokine CX3CL1 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D010455:Peptides; D019707:Receptors, Chemokine; D002118:Calcium