Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques

  • Inge De Meyer
  • Wim Martinet
  • Dorien M. Schrijvers
  • Jean-Pierre Timmermans
  • Hidde Bult
  • Guido R. Y. De Meyer
Original Contribution

DOI: 10.1007/s00395-012-0269-1

Cite this article as:
De Meyer, I., Martinet, W., Schrijvers, D.M. et al. Basic Res Cardiol (2012) 107: 269. doi:10.1007/s00395-012-0269-1

Abstract

Atherosclerotic plaques tend to rupture as a consequence of a weakened fibrous cap, particularly in the shoulder regions where most macrophages reside. Macrophages express Toll-like receptors to recognize pathogens and eliminate intracellular pathogens by inducing autophagy. Because Toll-like receptor 7 (TLR7) is thought to be expressed in macrophages but not in smooth muscle cells (SMCs), we investigated whether induction of macrophage autophagic death by TLR7 ligand imiquimod can affect the composition of atherosclerotic plaques in favor of their stability. Immunohistochemical staining of human carotid plaques as well as Western blotting of cultured macrophages and SMCs confirmed that TLR7 was expressed in macrophages, but not in SMCs. In vitro experiments showed that only TLR7 expressing cells underwent imiquimod-induced cell death, which was characterized by autophagosome formation. Imiquimod-treated macrophages activated nuclear factor-κB (NF-κB) and released pro-inflammatory cytokines and chemokines. This effect was inhibited by the glucocorticoid dexamethasone. Imiquimod-induced cytokine release was significantly decreased in autophagy-deficient macrophages because these cells died by necrosis at an accelerated pace. Local in vivo administration of imiquimod to established atherosclerotic lesions in rabbit carotid arteries induced macrophage autophagy without induction of cell death, and triggered cytokine production, upregulation of vascular adhesion molecule-1, infiltration of T-lymphocytes, accumulation of macrophages and enlargement of plaque area. Treatment with dexamethasone suppressed these pro-inflammatory effects in vivo. SMCs and endothelial cells in imiquimod-treated plaques were not affected. In conclusion, imiquimod induces macrophage autophagy in atherosclerotic plaques, but stimulates plaque progression through cytokine release and enhanced infiltration of inflammatory cells.

Keywords

Atherosclerosis Macrophage Autophagy Toll-like receptor 7 Inflammation 

Supplementary material

395_2012_269_MOESM1_ESM.docx (2.2 mb)
Supplementary material 1 (DOCX 2261 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Inge De Meyer
    • 1
  • Wim Martinet
    • 1
  • Dorien M. Schrijvers
    • 1
  • Jean-Pierre Timmermans
    • 2
  • Hidde Bult
    • 1
  • Guido R. Y. De Meyer
    • 1
  1. 1.Laboratory of PhysiopharmacologyUniversity of AntwerpAntwerpBelgium
  2. 2.Laboratory of Cell Biology and HistologyUniversity of AntwerpAntwerpBelgium

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