Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness.
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.


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.


CONCLUSIONS
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.
Schoneveld
A H
AH
Department of Cardiology, Experimental Cardiology Laboratory, UMC, Utrecht, The Netherlands.
Hoefer
I
I
Sluijter
J P G
JP
Laman
J D
JD
de Kleijn
D P V
DP
Pasterkamp
G
G
D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D005353:Fibronectins / Q000097:blood / Q000737:chemistry; D015870:Gene Expression / Q000276:immunology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001057:Apolipoproteins E; D005353:Fibronectins; D008024:Ligands; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4