Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, 120 University Place, Glasgow G12 8TA, United Kingdom.
Arterioscler Thromb Vasc Biol. 2012 Nov;32(11):2569-79. doi: 10.1161/ATVBAHA.112.251314. Epub 2012 Aug 30.
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.
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.
These results identify a critical role for pDCs in atherosclerosis and suggest a potential role for pDC targeting in the control of the pathology.
临床研究已经确定，循环中数量减少的浆细胞样树突状细胞（pDC）可作为冠心病心血管事件的预测因子，并且 pDC 可在人类动脉粥样硬化斑块的肩部区域检测到，在该区域最有可能发生破裂。动物模型的结果存在争议，pDC 被认为取决于实验条件而抑制或促进病变发展。在这里，我们研究了载脂蛋白 E 缺陷小鼠中 pDC 在动脉粥样硬化中的作用。
我们证明，载脂蛋白 E 缺陷和 C57BL/6 小鼠的主动脉和脾脏均显示出相似数量的 pDC，且具有相似的激活状态。相比之下，使用 Eα/Y-Ae 系统评估抗原摄取/呈递显示，载脂蛋白 E 缺陷（-）小鼠的主动脉 pDC 能够呈递体内系统给予的抗原。连续用抗小鼠浆细胞样树突状细胞抗原 1（mPDCA-1）抗体处理载脂蛋白 E 缺陷小鼠会导致主动脉和脾脏中 pDC 的特异性耗竭，并显著减少主动脉窦中的动脉粥样硬化形成（减少 46%；P<0.001）。pDC 的耗竭还减少了主动脉斑块中的巨噬细胞（减少 34%；P<0.05）和增加了胶原含量（增加 41%；P<0.05），暗示了更稳定的斑块表型。此外，pDC 耗竭减少了脾脏 T 细胞的激活，并抑制了白细胞介素-12、趋化因子（C-X-C 基序）配体 1、干扰素-γ 诱导的单核细胞因子、干扰素 γ 诱导蛋白 10 和血管内皮生长因子的血清水平。
这些结果确定了 pDC 在动脉粥样硬化中的关键作用，并表明针对 pDC 的靶向治疗可能在控制病理学方面发挥作用。
