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.

METHODS AND 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: Vincent Braunersreuther, Alma Zernecke, Claire Arnaud, Elisa A Liehn, Sabine Steffens, Erdenechimeg Shagdarsuren, Kiril Bidzhekov, Fabienne Burger, Graziano Pelli, Bruno Luckow, François Mach, Christian Weber
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 27 Issue 2 Pg. 373-9 (Feb 2007) ISSN: 1524-4636 [Electronic] United States
• PMID: 17138939 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• CCR1 protein, human
• Ccr1 protein, mouse
• Cholesterol, Dietary
• Cytokines
• Dietary Fats
• GATA3 Transcription Factor
• GATA3 protein, human
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• Membrane Proteins
• RNA, Messenger
• Receptors, CCR1
• Receptors, CCR5
• Receptors, Chemokine
• Receptors, Virus
• Interleukin-10

Topics

• Animals
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (genetics, metabolism, prevention & control)
• Carotid Stenosis (metabolism, physiopathology, prevention & control)
• Cell Proliferation
• Cholesterol, Dietary (adverse effects)
• Cytokines (metabolism)
• Dietary Fats (adverse effects)
• Female
• GATA3 Transcription Factor (genetics, metabolism)
• Gene Expression Regulation
• Hepatitis A Virus Cellular Receptor 2
• Interleukin-10 (genetics, metabolism)
• Lymph Nodes (cytology, metabolism)
• Membrane Proteins
• Mice
• Mice, Transgenic
• Phenotype
• RNA, Messenger (genetics, metabolism)
• Receptors, CCR1
• Receptors, CCR5 (genetics, metabolism)
• Receptors, Chemokine (genetics, metabolism)
• Receptors, Virus (genetics, metabolism)
• Spleen (cytology, metabolism)
• Th1 Cells (cytology, metabolism)