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 Ϫ/Ϫ ) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE Ϫ/Ϫ Ccr5 Ϫ/Ϫ mice, ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ 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 Ϫ/Ϫ Ccr5 Ϫ/Ϫ 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-␥ content were increased in ApoE Ϫ/Ϫ Ccr1 Ϫ/Ϫ mice. Conclusion-Genetic deletion of Ccr5 but not Ccr1 in ApoEϪ/Ϫ 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. (Arterioscler Thromb Vasc Biol.

Independent Roles of Monocyte Chemoattractant Protein-1, Regulated on Activation, Normal T-Cell Expressed and Secreted and Fractalkine in the Vulnerability of Coronary Atherosclerotic Plaques

“…29 Braunersreuther et al reported that RANTES plays a central role in promoting late-stage atherosclerosis in the context of accelerated atherosclerosis in ApoE -/-mice promoted by high-fat diet. 30 Fractalkine (CX3CL1) is a unique member of the CX3C chemokine subfamily. Accumulating evidence indicates CX3CL1/ CX3CR1 involvement in the pathogenesis of atherosclerosis.…”

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

“…However, given the redundancy of chemokine system, we cannot exclude that a chronic anti-chemokine treatment (i.e., Evasin-3) might induce a compensatory upregulation of other chemoattractants or chemokine receptors responsible for macrophage intraplaque recruitment. 26 Another limitation of the present study is represented by the assessment of mouse plaque vulnerability based on histologic surrogate biomarkers, instead of clinical cardiovascular outcomes (i.e., acute cerebral events). Since ApoE À / À mice have been shown to develop accelerated atherogenesis (also associated with microglial inflammation), [27][28][29] but not spontaneous ischemic events in the life time comparable to our shear stress-induced protocol (max 31 weeks of age), we were not able to assess carotid plaque vulnerability on the basis of a clinical thrombotic rupture.…”

Lentiviral gene transfer to reduce atherosclerosis progression by long-term CC-chemokine inhibition

“…2 CC-CKs including MCP-1, RANTES and MIP-1a are present in human atherosclerotic lesions. [3][4][5][6] In the atherosclerosis-prone apolipoprotein E knockout (ApoE-KO) mice, targeted deletion of single CC-CKs or CK receptors significantly reduces atherosclerotic plaque progression [7][8][9] demonstrating that a number of different CC-CK/CC-CK receptor interactions are important in atherosclerosis. Indeed, the marked functional redundancy in the CK/CK receptor signalling system suggests that a more broad-spectrum approach to CC-CK signaling may provide a more efficient strategy to reduce atherosclerosis.…”