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Updated: Jul 11, 2026
A Human Ex Vivo Atherosclerotic Plaque Model to Study Lesion Biology
Published on: May 6, 2014
Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness
A H Schoneveld1, I Hoefer, J P G Sluijter
1Department of Cardiology, Experimental Cardiology Laboratory, UMC, Utrecht, The Netherlands.
Background:
Toll like receptors (TLR) have been recognized for their role in atherosclerotic lesion development and progression. Endogenous TLR ligands that are also expressed in atherosclerotic tissues have been shown to promote atherosclerosis in mice. Since repetitive stimulation of TLR induces an attenuated inflammatory response, we hypothesized that the TLR response is altered during atherosclerosis development, due to chronic exposure to endogenous ligands.
Methods And Results:
We examined five groups of both ApoE-/- and C57Bl/6 mice aged 5, 10, 15, 25 and 40 weeks. In ApoE-/- mice with advanced stages of atherosclerosis, levels of mRNA encoding TLR2 and TLR4, the endogenous TLR ligands EDA and hsp60 as well as intracellular TLR-regulating mediators, like IRAK-M, were increased. Systemic TLR cell surface expression on circulating monocytes and EDA plasma levels were significantly increased in ApoE-/- mice with advanced atherosclerosis. We also observed that the endogenous TLR ligand EDA was capable of activating the TLR-signaling pathway in white blood cells. During the plaque progression stage however, stimulation of TLR2 and TLR4 in blood samples attenuated MIP-1 alpha and RANTES release in atherosclerotic mice.
Conclusion:
During atherosclerotic lesion development, TLR2 and TLR4 expression increases in atherosclerotic plaques and on circulating blood cells. However, with advanced stages of atherosclerotic disease, circulating blood cells become less responsive to TLR ligation, which may be due to chronic TLR engagement by endogenous EDA.
Insights
Toll-like receptor (TLR) expression increases in atherosclerosis, but chronic ligand exposure leads to reduced responsiveness in advanced disease. This suggests altered TLR signaling contributes to atherosclerosis progression.
Area of Science:
- Immunology
- Cardiovascular Research
- Atherosclerosis Pathogenesis
Background:
- Toll-like receptors (TLRs) are implicated in atherosclerotic lesion development.
- Endogenous TLR ligands present in atherosclerotic tissues can promote disease.
- Chronic TLR stimulation may attenuate inflammatory responses.
Purpose of the Study:
- To investigate alterations in the TLR response during atherosclerosis development.
- To examine the impact of chronic endogenous ligand exposure on TLR signaling.
Main Methods:
- Analysis of ApoE-/- and C57Bl/6 mice at various ages (5-40 weeks).
- Measurement of mRNA levels for TLR2, TLR4, EDA, hsp60, and IRAK-M.
- Assessment of systemic TLR cell surface expression and plasma EDA levels.
- Evaluation of TLR2 and TLR4 stimulation effects on inflammatory cytokine release (MIP-1 alpha, RANTES).
Main Results:
- Increased TLR2, TLR4, EDA, hsp60, and IRAK-M mRNA in advanced atherosclerosis (ApoE-/- mice).
- Elevated systemic TLR expression and plasma EDA in advanced atherosclerotic mice.
- EDA activated the TLR signaling pathway in white blood cells.
- TLR2 and TLR4 stimulation attenuated MIP-1 alpha and RANTES release during plaque progression.
Conclusions:
- TLR2 and TLR4 expression rises in atherosclerotic plaques and on circulating cells during lesion development.
- Circulating blood cells exhibit reduced responsiveness to TLR ligation in advanced atherosclerosis.
- Chronic engagement by endogenous EDA may cause this desensitization.
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