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-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-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.)
Original language | English (US) |
---|---|
Pages (from-to) | 1673-1683 |
Number of pages | 11 |
Journal | Circulation |
Volume | 125 |
Issue number | 13 |
DOIs | |
State | Published - Apr 3 2012 |
Keywords
- Atherosclerosis
- Dendritic cells
- Immune system
- Inflammation
- Leukocytes
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)