Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis

作者：Doering, Yvonne; Manthey, Helga D.; Drechsler, Maik; Lievens, Dirk; Megens, Remco T. A.; Soehnlein, Oliver; Busch, Martin; Manca, Marco; Koenen, Rory R.; Pelisek, Jaroslav; Daemen, Mat J.; Lutgens, Esther; Zenke, Martin; Binder, Christoph J.; Weber, Christian; Zernecke, Alma^*

来源：Circulation, 2012, 125(13): 1673-U190.

DOI：10.1161/CIRCULATIONAHA.111.046755

• atherosclerosis
• dendritic cells
• immune system
• inflammation
• leukocytes

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.)

• 出版日期2012-4-3