Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

Abstract

Background-Atherosclerosis is a systemic inflammatory disease characterized by the formation of atherosclerotic plaques. Both innate immunity and adaptive immunity contribute to atherogenesis, but the mode of interaction is poorly understood. Chemokine receptor 7 (CCR7) is critically involved in the transition from innate to adaptive immune activation by coordinating the migration to and positioning of antigen-presenting dendritic cells and T cells in secondary lymphoid organs. More recently, it was shown that CCR7 is also responsible for T-cell migration into inflamed tissues and T-cell egress from these tissues via the afferent lymph. Thus, we investigated the influence of a systemic CCR7 deficiency on atherogenesis in atherosclerosis-prone low-density lipoprotein receptor (ldlr) knockout mice. Methods and Results-CCR7 deficiency resulted in reduced atherosclerotic plaque development. CCR7Ϫ/Ϫ T cells showed impaired entry and exit behavior from atherosclerotic lesions. Oxidized low-density lipoprotein, a key molecule for atherogenesis with antigenic features, was used to pulse dendritic cells and to expand T cells ex vivo. Adoptive transfer of C57BL/6 wild-type T cells but not ccr7 Key Words: atherosclerosis Ⅲ lipids Ⅲ immune system Ⅲ lymphocytes A therosclerosis is a chronic systemic inflammatory disease characterized by the accumulation of lipids in the arterial wall, frequently leading to myocardial infarction, stroke, and sudden death. 1 In early atherogenesis, monocytes are recruited into the arterial vessel wall, where they differentiate into macrophages, take up cholesterol deposits (mainly oxidized low-density lipoproteins [oxLDL]), become foam cells, and form the initial atherosclerotic lesion. At the same time, secretion of inflammatory cytokines results in further recruitment of monocytes, T cells, and cells of the vessel wall into the lesion, thereby driving atherosclerotic plaque growth and maturation. Although there is profound evidence for the importance of both innate and adaptive immunity for atherosclerotic plaque development, 2 the transition processes and mode of interaction between these immune responses remain unclear. However, accumulating evidence indicates that oxLDL may represent a connecting piece between innate and adaptive immunity in this setting. In this regard, different groups were able to show that stimulation with oxLDL led not only to dendritic cell (DC) maturation 3,4 but also to clonal T-cell proliferation and differentiation into proinflammatory T helper (Th) 1 cells. 5,6 Clinical Perspective on p 1628The classic activation of adaptive immunity takes place in secondary lymphoid organs (SLOs) where antigen presentation by DCs to naïve T cells results in activation and functional differentiation of these T cells. The C-Cchemokine receptor type 7 (CCR7) has been described to be crucially involved in several fundamental processes shaping the structural and functional organization of the adaptive immune system. 7 CCR7 is regarded as a key receptor in the coordinated migrati...

CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice

“…Moreover, during hypercholesterolemia, DCs as well as CCL17 + DCs can be sequestered in the periphery (60) and may thus present antigens such as oxLDLor LDL-derived peptides in lymphoid tissue. Notably, a recent study employing Ccr7 -/-mice provided evidence supporting the hypothesis that local priming processes in the inflamed vessel wall or lymphoid tissue alone are insufficient to generate or maintain an adaptive immune response promoting atherogenesis; and that CCR7-dependent trafficking of T cells to draining LNs and their (re)entry to sites of inflammation are essential (61).…”

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

“…Other studies restricted monocyte entry using CX3CR1-deficient mice (21) or inhibited monocyte differentiation into DCs using GM-CSF-deficient mice (11) or restricted DC egress from lesions using CCR7-deficient mice (36). In all these mouse models, atherosclerosis was deceased, not increased as in the Cre + model, suggesting a proatherogenic role for DCs.…”

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

“…The role of CCR7 in atherogenesis is, however, more controversial due to the demonstration that CCR7 is important for macrophage emigration out of established atherosclerotic plaques in an aortic transplantation model of atherosclerosis (Trogan et al, 2006;Feig et al, 2010Feig et al, , 2011a. Ablation of the CCR7 gene in Ldlr 2/2 mice followed by 12 weeks of a high-fat diet was associated with reduced plaque size and reduced numbers of both CD68 1 cells (macrophages) and CD11c 1 cells [macrophages and DCs (Luchtefeld et al, 2010)]. An intriguing recent publication from the Fisher and Garabedian laboratories demonstrated that Apoe 2/2 mice a high-fat diet and treated with either atorvastatin or rosuvastatin demonstrated no change in atherosclerotic plaque area but did show significant reductions in CD68 1 macrophage staining area (Feig et al, 2011b).…”