Enhanced Expression of the Homeostatic Chemokines CCL19 and CCL21 in Clinical and Experimental Atherosclerosis

Damås, Jan Kristian; Smith, Camilla; Øie, Erik; Fevang, Børre; Halvorsen, Bente; Wæhre, Torgun; Boullier, Agnès; Breland, Unni M.; Yndestad, Arne; Ovchinnikova, Olga; Robertson, Anna-Karin L.; Sandberg, Wiggo J.; Kjekshus, John; Taskén, Kjetil; Frøland, Stig S.; Gullestad, Lars; Hansson, Göran K.; Quehenberger, Oswald; Aukrust, Pål

doi:10.1161/01.atv.0000255581.38523.7c

Cited by 127 publications

(126 citation statements)

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“…10 -12 Furthermore, CCL19 and CCL21 expression is enhanced within atherosclerotic lesions of apolipoprotein E-deficient mice and in human atherosclerotic carotid plaques. 12 Although delayed entry of ccr7 Ϫ/Ϫ T cells to peripheral sites of antigen exposure may contribute to reduced atherosclerotic plaque development, we speculated that injection of ex vivo primed T cells may restore atherogenesis by compensating the loss of CCR7-coordinated contact between antigen-presenting DCs and naïve T cells in SLOs. Given the autoantigenic potential and critical importance of oxLDL in atherogenesis, we used this molecule for ex vivo maturation and activation of DCs.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, recent studies suggested that the enhanced endothelial expression of CCR7 ligands in chronically inflamed organs 10,11 or within atherosclerotic lesions 12 causes sustained T-cell recruitment to sites of inflammation. 13,14 Moreover, because CCR7 deficiency results in accumulation of T cells in inflamed tissues, 9,15 T-cell egress from sites of inflammation into draining lymph nodes also depends on CCR7.…”

Section: Clinical Perspective On P 1628mentioning

confidence: 99%

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Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

et al. 2010

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective On P 1628mentioning

confidence: 99%

Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

et al. 2010

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“…Nevertheless, aortic arch lesions were only observed in aortas from PI3K␥ ϩ/ϩ 3 LDLR Ϫ/Ϫ mice (2% of aortic arch area) and not in PI3K␥ Ϫ/Ϫ 3 LDLR Ϫ/Ϫ mice. Genetic data have provided evidence for the importance of chemokine receptors in the early steps of atherosclerosis, because they recruit monocytes 22 and T cells, [23][24][25] which have been identified recently as key regulators of atherosclerosis. Several reports show that T-helper type 1-driven responses promote plaque formation, 26 -28 whereas natural regulatory T cells are able to attenuate these responses and decrease the progression of atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

et al. 2008

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Background-The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-␥ (PI3K␥) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3K␥ in the cardiovascular system suggest that PI3K␥ plays a role in atherosclerosis. Methods and Results-Here, we demonstrate that a specific PI3K␥ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient mice. Furthermore, PI3K␥ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor-deficient mice transplanted with wild-type or PI3K␥-deficient bone marrow demonstrated that functional PI3K␥ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3K␥ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. Conclusions-These data identify PI3K␥ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.

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“…68,69 A possible role for these chemokines and their receptor CCR7 in atherosclerosis has recently been addressed in 3 separate studies with contradictory findings. Compared to healthy controls, both CCL19 and CCL21 were increased in plasma and within carotid atherosclerotic lesions of patients with stable angina and even further in those with unstable CAD and in plaques of Apoe Ϫ/Ϫ mice.…”

Section: Immune-regulatory Chemokines Ccl19 and Ccl21 In Vascular Dismentioning

confidence: 99%

Chemokines in Atherosclerosis

Zernecke

Shagdarsuren

Weber

2008

ATVB

346

220

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Abstract-The fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site-and stage-specific effects of T cell-activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX 3 CL1 and CXCL16 with their respective receptors CX 3 CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected.

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Enhanced Expression of the Homeostatic Chemokines CCL19 and CCL21 in Clinical and Experimental Atherosclerosis

Abstract: The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

Cited by 127 publications

References 30 publications

Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

Chemokine Receptor 7 Knockout Attenuates Atherosclerotic Plaque Development

Genetic and Pharmacological Targeting of Phosphoinositide 3-Kinase-γ Reduces Atherosclerosis and Favors Plaque Stability by Modulating Inflammatory Processes

Chemokines in Atherosclerosis

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