Scientific article

An engineered CX3CR1 antagonist endowed with anti-inflammatory activity

Published inJournal of leukocyte biology, vol. 86, no. 4, p. 903-911
Publication date2009

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.

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
  • CHO Cells
  • Calcium/metabolism
  • Cell Adhesion/drug effects
  • Chemokine CX3CL1/metabolism
  • Chemotaxis/*drug effects
  • Cricetinae
  • Cricetulus
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Inflammation/drug therapy/metabolism
  • Macrophages, Peritoneal/*metabolism
  • Mice
  • Peptides/*pharmacology
  • Peritonitis/drug therapy/metabolism
  • Receptors, Chemokine/*antagonists & inhibitors/metabolism
Research group
Citation (ISO format)
DORGHAM, Karim et al. An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. In: Journal of leukocyte biology, 2009, vol. 86, n° 4, p. 903–911. doi: 10.1189/jlb.0308158
Main files (1)
ISSN of the journal0741-5400

Technical informations

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