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Toll-like receptors in atherosclerosis

P S Tobias1, L K Curtiss

  • 1Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Biochemical Society Transactions
|November 23, 2007
PubMed

Insights

Toll-like receptors (TLRs) link inflammation and atherosclerosis. TLR2 activation by various agents promotes atherosclerosis in hyperlipidaemic mice, involving both bone-marrow-derived cells and other cell types.

Area of Science:

  • Immunology
  • Cardiovascular Research
  • Molecular Biology

Background:

  • Atherosclerosis is now understood as a chronic inflammatory disease of the arterial wall, not merely a lipid storage issue.
  • Innate immune mechanisms, particularly Toll-like receptors (TLRs), are implicated in atherosclerosis due to links with hyperlipidaemia and infection.
  • Oxidized lipids and infectious agents can act as ligands for TLRs, potentially initiating or exacerbating inflammation in atherosclerosis.

Purpose of the Study:

  • To investigate the role of Toll-like receptor 2 (TLR2) in the development of atherosclerosis.
  • To identify the cellular sources of proatherogenic TLR2 responses in hyperlipidaemic conditions.
  • To differentiate TLR2-mediated inflammatory pathways involving bone-marrow-derived cells (BMDC) versus non-BMDC.

Main Methods:

  • Utilized murine models of atherosclerosis, specifically mice deficient in low-density lipoprotein receptor.
  • Administered defined synthetic agonists (Pam3 CSK4) and studied responses to unknown endogenous/exogenous agonists.
  • Differentiated cellular contributions by analyzing responses in bone-marrow-derived cells (BMDC) and non-BMDC, including endothelial cells.

Main Results:

  • Demonstrated a significant role for TLR2 in promoting atherosclerosis in hyperlipidaemic mice.
  • Showed that proatherogenic TLR2 responses to endogenous or unknown exogenous agonists are mediated by non-BMDC.
  • Identified that TLR2 responses to the synthetic agonist Pam3 CSK4 are partly mediated by BMDC, including monocytes/macrophages and dendritic cells.

Conclusions:

  • TLR2 activation by both endogenous and exogenous agents contributes to atherosclerosis in hyperlipidaemic mice.
  • Both bone-marrow-derived cells and non-bone-marrow-derived cells, such as endothelial cells, mediate proatherogenic TLR2 signaling.
  • Targeting TLR2 pathways presents a potential therapeutic strategy for atherosclerosis prevention and treatment.

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