title: Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice.
abstract: OBJECTIVE
  Chemokines and their receptors are crucially involved in the development of atherosclerotic lesions by directing monocyte and T cell recruitment. The CC-chemokine receptors 1 (CCR1) and 5 (CCR5) expressed on these cells bind chemokines implicated in atherosclerosis, namely CCL5/RANTES. Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined.
  
  
  RESULTS
  We provide two independent lines of investigation to dissect the effects of Ccr1 and Ccr5 deletion in apolipoprotein E-deficient (ApoE-/-) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE-/- Ccr5-/- mice, ApoE-/- Ccr1-/- mice or respective littermates, were fed a high-fat diet for 10 to 12 weeks. Plaque areas were quantified in the aortic roots and thoracoabdominal aortas. Concordantly, both laboratories found that lesion formation was reduced in ApoE-/- Ccr5-/- mice. Plaque quality and immune cells were assessed by immunohistochemistry or mRNA analysis. Whereas lesional macrophage content, aortic CD4, and Th1-related Tim3 expression were reduced, smooth muscle cell (SMC) content and expression of interleukin-10 in plaques, lesional SMCs, and splenocytes were elevated. Protection against lesion formation by Ccr5 deficiency was sustained over 22 weeks of high-fat diet or over 26 weeks of chow diet. Conversely, plaque area, T cell, and interferon-gamma content were increased in ApoE-/- Ccr1-/- mice.
  
  
  CONCLUSIONS
  Genetic deletion of Ccr5 but not Ccr1 in ApoE-/- mice protects from diet-induced atherosclerosis, associated with a more stable plaque phenotype, reduced mononuclear cell infiltration, Th1-type immune responses, and increased interleukin-10 expression. This corroborates CCR5 as a promising therapeutic target.
authors.affiliation: Division of Cardiology, Foundation for Medical Research, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
authors.forename: Kiril
authors.initials: K
authors.lastname: Bidzhekov
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Bruno
authors.initials: B
authors.lastname: Luckow
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016893:Carotid Stenosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D049109:Cell Proliferation; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D002791:Cholesterol, Dietary; D016207:Cytokines; D004041:Dietary Fats; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D016753:Interleukin-10