Plasmacytoid Dendritic Cells Play a Key Role in Promoting Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract

Objective-Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E−deficient mice. Methods and Results-We demonstrated that the aorta and spleen of both apolipoprotein E−deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Eα/Y-Ae system revealed that aortic pDCs in apolipoprotein E−deficient -mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E−deficient mice with anti−mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%; P<0.001). Depletion of pDCs also reduced macrophages (by 34%; P<0.05) and increased collagen content (by 41%; P<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon-γ, interferon γ−induced protein 10, and vascular endothelium growth factor serum levels. Conclusion-These

Dendritic Cells in Cardiovascular Diseases

“…pDCs isolated from atherosclerotic mice suppressed CD4 + T-cell proliferation in an indoleamine-2,3-dioxygenasedependent manner, suggestive of an atheroprotective role for pDCs in atherosclerosis. 53 In contrast to our study, Döring and colleagues 28 and MacRitchie and colleagues, 54 as well, reported significantly decreased diet-induced lesion formation in the aortic root and the aorta of pDC-depleted ApoE −/− mice, whereas plaques showed a more stable phenotype. Both groups investigated the impact of pDC depletion by use of the PDCA-1 depletion antibody on early lesion development (4 weeks of high-fat diet feeding).…”

“…In line with this, Döring and colleagues 28 showed that sorted aortic pDCs from hyperlipidemic mice, ex vivo primed, were capable of triggering T-cell stimulation in vivo. Finally, baseline IFN-α levels were below detection levels or not affected by pDCs in our study and the study of MacRitchie and coworkers, 53,54 whereas Döring and colleagues 28 demonstrated elevated IFN-α levels in plaque (mRNA) and serum in high-fat diet-fed ApoE −/− mice, being reduced after pDC depletion. It must be noted that these groups used different methodologies, such as the use of the depletion antibody, administration regimen, and mouse models.…”

“…Whereas pDCs could barely be detected in mouse atherosclerotic lesions in Ldlr −/− mice, 53 they were detected in lesions of ApoE −/− mice, mainly in the plaque shoulder, at which pDC abundance was increased with high-fat diet feeding and lesion progression. 28 Conversely, MacRitchie and colleagues 54 described the constitutive presence of mostly immature pDCs in noninflamed aortic tissue of normolipidemic mice, at numbers similar to those seen in atherosclerotic ApoE −/− mice. Nevertheless, the antigen presentation capacity of aortic pDCs from ApoE −/− mice was enhanced.…”

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

“…Thus, deletion of MyD88 in CD11c-expressing macrophages in atherosclerotic lesions (13) could potentially decrease lesional inflammation and thus suppress atherosclerosis. If this were the case, the data herein would indicate that the proatherogenic effects of MyD88 depletion in CD11c + DCs are dominant over the potentially antiatherogenic effects of MyD88 depletion in CD11c + macrophages.…”

“…Thus, the net effect of DC-mediated T cell activation on atherogenesis would depend on the type(s) of T cells that is activated in the environmental and antigen context of atherosclerosis. Most mouse studies in which DCs have been depleted or disabled show a decrease in atherosclerosis, suggesting that a major role of DCs is activation of proatherogenic T effector (Teff) cells (10)(11)(12)(13). On the other hand, a recent study showed that deletion of Flt3, which results in defective development of conventional DCs, a decrease in lesional CD103 + DCs, and a systemic decrease in Tregs, is associated with an increase in atherosclerosis (14).…”