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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)903-911
Number of pages9
JournalJournal of Leukocyte Biology
Volume86
Issue number4
DOIs
Publication statusPublished - Oct 1 2009

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Cell Biology

Fingerprint Dive into the research topics of 'An engineered CX3CR1 antagonist endowed with anti-inflammatory activity'. Together they form a unique fingerprint.

  • Cite this

    Dorgham, K., Ghadiri, A., Hermand, P., Rodero, M., Poupel, L., Iga, M., Hartley, O., Gorochov, G., Combadière, C., & Deterre, P. (2009). An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. Journal of Leukocyte Biology, 86(4), 903-911. https://doi.org/10.1189/jlb.0308158