Conclusions:The bacterial debris observed in human atheroma, which is currently considered to be harmless, may have potential to contribute to disease progression via TLR-dependent lipid body formation in macrophages.
TLR stimulation promotes the accumulation of lipid bodies in macrophages and consequently foam cell formation. The pathways responsible for these processes may constitute novel therapeutic targets for atherosclerosis.
We and others have shown that the molecular signatures of diverse bacterial species accumulate in human atheromatous lesions. Here, we aimed to determine the effect of non-viable bacteria on foam cell formation in vitro. Using human monocyte-derived macrophages and the murine J774 macrophage cell line, we found that any of a diverse panel of heat-killed Gram-positive or Gram-negative bacteria shown previously to accumulate in human atherosclerotic lesions promoted marked induction of foam cell formation in macrophages, as assessed by light-microscopy of Oil-red-O stained cells and Nile-red-based flow cytometric quantification of cellular lipid accumulation. As Toll-like receptors (TLRs) have a central role in the induction of inflammatory signalling by bacteria, we next examined if specific TLR-ligands could also promote foam cell formation in the absence of intact bacteria. Remarkably, stimulation of macrophages with purified ligands specific for any of the TLRs (including lipopeptide, polyI:C, LPS, flagellin, ssRNA, loxoribine and CpG DNA) led to significant lipid accumulation. This process was not dependent on oxidation of low-density lipoprotein (LDL) as neither antioxidants nor the scavenger receptor blocker polyinosinic acid reduced foam cell formation. Moreover, the presence of LDL was not required for TLR-mediated foam cell formation. Specific inhibitors of TLR signalling prevented foam cell formation induced by TLR ligands or bacteria. We conclude that although the bacterial signatures present in human atheroma are likely to reflect non-viable, killed organisms, it remains possible that molecules derived from these organisms may promote the differentiation of macrophages to lipid-laden foam cells via mechanisms that are likely to include stimulation of TLRs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.