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

Circulation. 2012 Apr 3;125(13):1673-83. doi: 10.1161/CIRCULATIONAHA.111.046755. Epub 2012 Mar 2.


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.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / immunology*
  • Atherosclerosis / metabolism
  • Autoantigens / genetics
  • Autoantigens / immunology*
  • Carotid Stenosis / genetics
  • Carotid Stenosis / immunology
  • Carotid Stenosis / metabolism
  • DNA / genetics
  • DNA / immunology*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteins / genetics*
  • Proteins / immunology*


  • Autoantigens
  • Proteins
  • DNA