Oxidized low-density lipoprotein-induced apoptotic dendritic cells as a novel therapy for atherosclerosis

Vanessa Frodermann, Gijs H M van Puijvelde, Laura Wierts, H Maxime Lagraauw, Amanda C Foks, Peter J van Santbrink, Ilze Bot, Johan Kuiper, Saskia C A de Jager

Research output: Contribution to journalArticleAcademicpeer-review


Modulation of immune responses may form a powerful approach to treat atherosclerosis. It was shown that clearance of apoptotic cells results in tolerance induction to cleared Ags by dendritic cells (DCs); however, this seems impaired in atherosclerosis because Ag-specific tolerance is lacking. This could result, in part, from decreased emigration of DCs from atherosclerotic lesions because of the high-cholesterol environment. Nonetheless, local induction of anti-inflammatory responses by apoptotic cell clearance seems to dampen atherosclerosis, because inhibition of apoptotic cell clearance worsens atherosclerosis. In this study, we assessed whether i.v. administration of oxLDL-induced apoptotic DCs (apop(ox)-DCs) and, as a control, unpulsed apoptotic DCs could modulate atherosclerosis by inducing tolerance. Adoptive transfer of apop(ox)-DCs into low-density lipoprotein receptor knockout mice either before or during feeding of a Western-type diet resulted in increased numbers of CD103(+) tolerogenic splenic DCs, with a concomitant increase in regulatory T cells. Interestingly, both types of apoptotic DCs induced an immediate 40% decrease in Ly-6C(hi) monocyte numbers and a 50% decrease in circulating CCL2 levels, but only apop(ox)-DC treatment resulted in long-term effects on monocytes and CCL2 levels. Although initial lesion development was reduced by 40% in both treatment groups, only apop(ox)-DC treatment prevented lesion progression by 28%. Moreover, progressed lesions of apop(ox)-DC-treated mice showed a robust 45% increase in collagen content, indicating an enhanced stability of lesions. Our findings clearly show that apoptotic DC treatment significantly decreases lesion development, but only apop(ox)-DCs can positively modulate lesion progression and stability. These findings may translate into a safe treatment for patients with established cardiovascular diseases using patient-derived apop(ox)-DCs.

Original languageEnglish
Pages (from-to)2208-2218
Number of pages11
JournalJournal of Immunology
Issue number5
Publication statusPublished - 2015


  • Adaptive Immunity
  • Animals
  • Antigens, Ly
  • Apoptosis
  • Atherosclerosis
  • Chemokine CCL2
  • Collagen
  • Dendritic Cells
  • Gene Expression Regulation
  • Immune Tolerance
  • Immunotherapy, Adoptive
  • Lipoproteins, LDL
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • Plaque, Atherosclerotic
  • Primary Cell Culture
  • Receptors, LDL
  • Signal Transduction
  • T-Lymphocytes, Regulatory


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