Toll-like receptors in atherosclerosis.
At one time, atherosclerosis was thought to be a simple lipid storage disease. However, it is now recognized as a chronic and progressive inflammation of the arterial wall. Gene deletion experiments in murine models of atherosclerosis that reduce the inflammatory process also reduce disease severity. Identifying the initiators and mediators of that inflammation can provide promising avenues for prevention or therapy. Two prominent risk factors, hyperlipidaemia and infectious disease, point to innate immune mechanisms as potential contributors to proatherogenic inflammation. The TLRs (Toll-like receptors), pro-inflammatory sensors of pathogens, are potential links between inflammation, infectious disease and atherosclerosis. A mechanism for hyperlipidaemic initiation of sterile inflammation can be postulated because oxidized lipoproteins or their component oxidized lipids have been identified as TLR ligands. Moreover, infectious agents are correlated with atherosclerosis risk. We have identified a role for TLR2 in atherosclerosis in mice deficient in low-density lipoprotein receptor. We observed that proatherogenic TLR2 responses to unknown endogenous or unknown endemic exogenous agonists are mediated by non-BMDC (bone-marrow-derived cells), which can include endothelial cells. In contrast, the proatherogenic TLR2 responses to the defined synthetic exogenous agonist Pam3 CSK4 are mediated at least in part by BMDC, which can include lymphocytes, monocytes/macrophages and dendritic cells. TLR2-mediated cell activation in response to endogenous and exogenous agents is proatherogenic in hyperlipidaemic mice.
Tobias
P S
PS
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Curtiss
L K
LK
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000172:deficiency / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*
D008024:Ligands; D011973:Receptors, LDL; D051195:Toll-Like Receptor 2