CX ₃ CR1 Deficiency Impairs Dendritic Cell Accumulation in Arterial Intima and Reduces Atherosclerotic Burden

Abstract

Objective-Dendritic cells (DCs) have recently been found in atherosclerosis-predisposed regions of arteries and have been proposed to be causal in atherosclerosis. The chemokine receptor CX 3 CR1 is associated with arterial injury and atherosclerosis. We sought to determine whether a link exists between arterial DC accumulation, CX 3 CR1, and atherosclerosis. Methods and Results-Mouse aortas were isolated and subjected to en face immunofluorescence analysis. We found that DCs were located predominantly in the intimal regions of arterial branch points and curvatures. Consistent with the increased accumulation of intimal DCs in aged and ApoE Ϫ/Ϫ aortas compared with young WT aortas (Pϭ0.004 and 0.05, respectively), the incidence of atherosclerosis was 88.9% for aged WT and 100% for ApoE Ϫ/Ϫ mice compared with 0% for young WT mice. CX 3 CR1 was expressed on intimal DCs and DC numbers were decreased in CX 3 CR1-deficient aortas of young, aged, and ApoE Ϫ/Ϫ mice (Pϭ0.0008, 0.013, and 0.0099). The reduced DC accumulation in CX 3 CR1-deficiency was also correlated with decreased atherosclerosis in these animals. Conclusions-The accumulation of intimal DC increases in aged and ApoEϪ/Ϫ aortas and correlates with the generation of atherosclerosis. CX 3 CR1-deficiency impairs the accumulation of DC in the aortic wall and markedly reduces the atherosclerotic burden. While macrophages uptake oxidized low-density lipoprotein (oxLDL) through scavenger receptors 1 to perform the first line of host defense, antigen-specific T cells influx in atherosclerotic lesions to elicit an adaptive immune response. 2 Although macrophages are capable of presenting antigens to T cells, dendritic cells (DCs) are the only antigen-presenting cell capable of activating the naïve T cell, thereby playing a crucial role in triggering adaptive immunity.Recently, DCs have been identified in atherosclerotic plaques in patients with atherosclerosis 3,4 and in animal models of atherosclerosis. 5,6 DCs have been suggested to participate in the immune response in advanced atheroma by colocalizing with T cells. 4 Interestingly, DCs have also been detected in the arterial intima of healthy young children 7 and in normal wild-type mice, 8 giving rise to the intriguing possibility that preexisting DCs in the arterial wall contribute to the generation of atherosclerosis.Monocytes are major precursors of vascular macrophages and DCs, and the chemokine receptor CX 3 CR1 with its ligand CX 3 CL1 (fractalkine) is a key regulator of monocyte adhesion and migration. CX 3 CR1 is expressed on monocytes, 9 whereas CX 3 CL1 is a transmembrane chemokine on activated endothelium. 10 Membrane-tethered CX 3 CL1 mediates the rapid capture and firm adhesion of monocytes under physiological conditions. 11 CX 3 CL1 can also be shed by proteolysis to act as a potent chemoattractant. 12,13 Both human genetic studies and animal models have implicated an important role for CX 3 CR1 and CX 3 CL1 in atherosclerosis. In humans, a polymorphism of CX 3 CR1 coding for a dysfunctional rece...

T Cell CX3CR1 Mediates Excess Atherosclerotic Inflammation in Renal Impairment

“…[4][5][6][7] Absence of CX3CR1 (CX3CR1 gfp/gfp , termed CX3CR1 2/2 throughout this manuscript) impeded atherosclerosis development as previously reported. [23][24][25] In addition, it completely prevented an increase of lesion size in renal impairment in all parts of the aortic vessel, namely aortic arch, thoracic, and abdominal aorta ( Figure 1B). Changes in male and female mice were very similar (Supplemental Figure 1, A and B).…”

“…21 CX3CR1 deficiency (CX3CR1 2/2 , mostly studied in CX3CR1 gfp/gfp mice 22 ) decreases the development of atherosclerotic lesions in Apoe 2/2 mice. [23][24][25] This protection is transferred by deficient bone marrow, indicating a major role of myeloid CX3CR1 in lesion development. 26 In Apoe 2/2 and LDLr 2/2 mice, pharmacologic CX3CR1 inhibition moderately decreases aortic root lesion size.…”

Divergent Role of Donor Dendritic Cells in Rejection versus Tolerance of Allografts

“…20 We are first to show the importance of the CX3CR1 pathway in the generation of heart DC. Unexpectedly, administration of MR1 or CTLA4-Ig did not improve the engraftment of CX3CR1 Ϫ/Ϫ donor hearts.…”

Tolerization against atherosclerosis using heat shock protein 60

“…For example, it has been demonstrated in several studies that T cells are one of the first cells to invade the arterial intima, later followed by macrophages, DCs, and SMCs in predisposed sites (Xu et al 1990;Kleindienst et al 1993;Millonig et al 2002). However, it has been shown that preexisting vascularassociated dendritic cells (VADCs) are presented in the tertiary lymphoid structures in the aortic adventitia at predisposed sites, even before the invasion of T cells (Bobryshev andLord 1996, 1998;Waltner-Romen et al 1998;Millonig et al 2001a, b;Liu et al 2008;Bobryshev 2010;Cybulsky and JongstraBilen 2010). These DCs can function as antigen-presenting cells (APCs) and thereby capture potentially harmful exogenous or autoantigens and present these to T cells and macrophages.…”