Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis
Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis
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DOI：
10.1161/circulationaha.111.046755
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发表时间：
2012-04-03
期刊：
影响因子：
37.8
通讯作者：
Zernecke, Alma
中科院分区：
文献类型：
--
作者：
Doering, Yvonne;Manthey, Helga D.;Zernecke, Alma
背景--在动脉粥样硬化中，炎症与自身免疫过程密切相关。在自身免疫性疾病中，浆细胞样树突状细胞(plmacytoid Dendritic cell，PDCs)不仅能在致病单链核酸的作用下产生I型干扰素，还能感知死亡细胞释放的自身DNA或与抗菌肽Cramp/LL37结合的中性粒细胞外陷阱中的自身DNA。然而，pDC在动脉粥样硬化中的确切作用仍不清楚。方法和结果--在这里，我们证明在小鼠和人的动脉粥样硬化病变中可以检测到pDC。暴露于氧化修饰的低密度脂蛋白可增强pDC吞噬细胞和抗原特异性T细胞反应的能力。Cramp/DNA复合体可以刺激浆细胞样树突状细胞产生干扰素-α，我们进一步证实在动脉粥样硬化的动脉中，Cramp的表达增加和中性粒细胞胞外陷阱的形成。虽然Cramp/DNA复合体加剧了载脂蛋白E缺陷小鼠动脉粥样硬化病变的形成，但骨髓中PDC耗竭和Cramp缺陷降低了动脉粥样硬化和抗双链DNA抗体效价。此外，pDC的特异性激活和干扰素-α治疗促进了斑块的生长，与增强的抗双链DNA抗体滴度有关。相应地，有症状和无症状颈动脉狭窄患者的抗双链DNA抗体升高。结论动脉粥样硬化病变中自身DNA(如从死亡细胞或中性粒细胞外陷阱释放)和抗菌肽Cramp/LL37的表达增加，可能刺激PDC驱动的自身免疫激活途径和抗双链DNA抗体的产生，严重加重动脉粥样硬化病变的形成。因此，这些关键因素可能代表着新的治疗靶点。(发行量。2012；125：1673-1683。)
Background-Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid dendritic cells (pDCs) are specialized to produce type-I interferons in response to pathogenic single-stranded nucleic acids, but can also sense self-DNA released from dying cells or in neutrophil extracellular traps complexed to the antimicrobial peptide Cramp/LL37 in autoimmune disease. However, the exact role of pDCs in atherosclerosis remains elusive.Methods and Results-Here we demonstrate that pDCs can be detected in murine and human atherosclerotic lesions. Exposure to oxidatively modified low-density lipoprotein enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. Plasmacytoid DCs can be stimulated to produce interferon-alpha by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of neutrophil extracellular traps in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-double-stranded DNA antibody titers. Moreover, the specific activation of pDCs and interferon-alpha treatment promoted plaque growth, associated with enhanced anti-double-stranded-DNA antibody titers. Accordingly, anti-double-stranded DNA antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.Conclusions-Self-DNA (eg, released from dying cells or in neutrophil extracellular traps) and an increased expression of the antimicrobial peptide Cramp/LL37 in atherosclerotic lesions may thus stimulate a pDC-driven pathway of autoimmune activation and the generation of anti-double-stranded-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets. (Circulation. 2012; 125: 1673-1683.)