Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis

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 and Zernecke, Alma (2012) Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation, 125 13: 1673-1683. doi:10.1161/CIRCULATIONAHA.111.046755

Author 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
Title Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis
Journal name Circulation   Check publisher's open access policy
ISSN 0009-7322
Publication date 2012-04-03
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.111.046755
Open Access Status Not yet assessed
Volume 125
Issue 13
Start page 1673
End page 1683
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted abstract
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-α 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-α 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.

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.
Keyword Atherosclerosis
Dendritic cells
Immune system
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Australian Institute for Bioengineering and Nanotechnology Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 141 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 138 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 24 Mar 2017, 11:46:57 EST by Miss Helga Manthey on behalf of Learning and Research Services (UQ Library)