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...

CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2−/− mice compared to WT controls (p = 0.017), whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2–6-fold elevated in the serum and 22–28-fold increased in the arthritic joints in CCR2−/− mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints). Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2−/− mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2−/− mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2−/− mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.

Th17 cells have been implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). Chemokine receptor CCR2 mediates leukocyte trafficking to sites of inflammation and is considered to be an important proinflammatory factor in RA. However, as an unexpected paradox, mice lacking CCR2 (CCR2-/-) develop an accelerated and enhanced arthritis in the collagen induced arthritis model (CIA). To investigate the underlying mechanism(s), we examined the role of Th17 cells in CCR2-/- mice with CIA. We found that the number of Th17 cells was increased significantly in draining lymph nodes of CCR2-/- CIA mice (845±144) compared to WT controls (289±136, p=0.017). In contrast, Th1 cells were not significantly different between groups (485±171 vs. 516±86 for WT, p=0.88). Consistently, CCR2-/- CIA mice had elevated levels of sera IL-17 (84.4±15.5 pg/ml) and IL-17 mRNA in arthritic joints (3.43±0.61 fold) compared to WT mice (45±9.7 pg/ml in the serum and 0.21±0.05 fold in the joint, p=0.04 and 0.009 respectively). Furthermore, Th17-favored cytokines IL-6 and IL-1β were up-regulated in the serum of CCR2-/- animals (IL-6: 366.1±54.5 pg/ml vs. 58.7±13.3 pg/ml for WT, p=0.0004; IL-1β: 189.6±21.9 pg/ml vs. 106.4±21.3 pg/ml for WT, p=0.01). These data suggest that Th17 cells contribute to the pathogenesis of the aggravated phenotype of autoimmune arthritis in CCR2-/- mice. Mice deficient in CCR2 may serve as a model for evaluations of anti-Th17 therapies against RA.

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