Lipopolysaccharide, Toll-Like Receptors, and the Immune Contribution to Atherosclerosis

Abstract

To the Editor: Stoll and colleagues present an intriguing and timely review on the potential contribution of lipopolysaccharide (LPS) to development of atherosclerotic plaque.1 Recent studies have now provided important new insights into how LPS and other pathogen-associated molecular patterns (PAMPs) might directly contribute to atherosclerosis and suggest that the contribution of immune mechanisms to atherogenesis may be more important that presently realized. Walton et al reported that modified but not native low-density lipoproteins (LDL) upregulate TLR4 in endothelial cells, are recognized by TLR4 in a CD14-independent fashion, and cause increased endothelial cell expression of IL-8.2 Studies from Witztum’s laboratory indicate that modified LDL signals mediated by TLR4 cause actin polymerization and spreading of macrophages that results in decreased phagocytosis of apoptotic cells and enhanced uptake of modified LDL.3 Recent in vivo studies provide more direct insights in the role of TLR signaling events in atherosclerosis. Bjorkbacka et al reported that genetic deficiency of CD14 in apolipoprotein E (apoE)-null mice had no effect on early lesion development.4 Because CD14 seems to be important for LPS-induced TLR4 signaling, this might at first imply that TLR4 signaling is not involved in atherosclerosis. However, results from our laboratory showed that TLR4−/−apoE−/− mice demonstrated reduced atherosclerosis.5 These findings collectively are most consistent with the interpretation that TLR4 signaling contributes to atherosclerosis, and either LPS is not the …