Auto-Antigenic Protein-DNA Complexes Stimulate Plasmacytoid Dendritic Cells to Promote Atherosclerosis
Background—Inflammation has been closely linked to auto-immunogenic processes in atherosclerosis. Plasmacytoid DCs (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 (NETs) 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 oxLDL enhanced the capacity of pDCs to phagocytose and prime antigen-specific T cell responses. pDCs can be stimulated to produce IFN-α by Cramp/DNA complexes, and we further identified increased expression of Cramp and formation of NETs in atherosclerotic arteries. Whereas Cramp/DNA complexes aggravated atherosclerotic lesion formation in apolipoprotein E-deficient (Apoe-/-) mice, pDC depletion and Cramp-deficiency in bone marrow reduced atherosclerosis and anti-dsDNA antibody titers. Moreover, the specific activation of pDCs and IFN-α treatment promoted plaque growth, associated with enhanced anti-ds-DNA antibody titers. Accordingly, anti-dsDNA-antibodies were elevated in patients with symptomatic versus asymptomatic carotid artery stenosis.
Conclusions—Self-DNA, e.g. released from dying cells or in NETs, 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-ds-DNA antibodies, critically aggravating atherosclerosis lesion formation. These key factors may thus represent novel therapeutic targets.
- Received June 1, 2011.
- Accepted February 22, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited