An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Karim Dorgham, Ata Ghadiri, Patricia Hermand, Mathieu Rodero, Lucie Poupel, Mutsumori Iga, Oliver Hartley, Guy Gorochov, Christophe Combadière, Philippe Deterre

研究成果: Contribution to journalArticle査読

60 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)903-911
ページ数9
ジャーナルJournal of Leukocyte Biology
86
4
DOI
出版ステータス出版済み - 10 2009

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学
  • 細胞生物学

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