title: Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice.
abstract: OBJECTIVE
  Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis.
  
  
  RESULTS
  Treatment with F1, an amino terminus-modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both Apoe(-/-) and Ldlr(-/-) proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated Apoe(-/-) mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated Apoe(-/-) mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of Apoe(-/-) mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype.
  
  
  CONCLUSIONS
  The CX3CR1 antagonist F1 is a potent inhibitor of the progression of atherosclerotic lesions by means of its selective impact on inflammatory monocyte functions. Controlling monocyte trafficking and survival may be an alternative or complementary therapy to lipid-lowering drugs classically used in the treatment of atherosclerosis.
authors.affiliation: From UMR_S 945, Laboratoire "Immunité et Infection," Inserm Paris, France and Université Pierre et Marie Curie- (UPMC) Paris 6, Paris, France (L.P., A.B., P.H., K.D., E.G., C.A., P.D., C.C.); UMR_S 939 P.LUMR_S 939, Laboratoire "Dyslipidémies, Inflammation et Athérosclérose," Paris, France (F.S.C., P.L.); and AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service d'Immunologie, Paris, France (C.C.).
authors.forename: Lucie
authors.initials: L
authors.lastname: Poupel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Boissonnas
authors.forename: Patricia
authors.initials: P
authors.lastname: Hermand
authors.forename: Karim
authors.initials: K
authors.lastname: Dorgham
authors.forename: Elodie
authors.initials: E
authors.lastname: Guyon
authors.forename: Constance
authors.initials: C
authors.lastname: Auvynet
authors.forename: Flora Saint
authors.initials: FS
authors.lastname: Charles
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
authors.forename: Philippe
authors.initials: P
authors.lastname: Deterre
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadiere
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010455:Peptides / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; C584583:F1 CX3CR1 ligand peptide; D000960:Hypolipidemic Agents; D008024:Ligands; D010455:Peptides; D019707:Receptors, Chemokine; D011973:Receptors, LDL
keywords: CX3CR1 protein, mouse; atherosclerosis; chemokine receptors; migration, cell; monocytes; receptor antagonist