BS79 Investigation of the contribution of non-canonical inflammasome activation to LPS-induced foam cell formation in macrophages

BackgroundBacterial lipopolysaccharide (LPS) has been shown to accelerate atherosclerosis when administered parenterally to mice, and also to promote foam cell formation in macrophages cultured in vitro. However, it is not clear how LPS signaling promotes lipid accumulation in macrophages. We found that although LPS-induced foam cell formation was lower in Tlr4-/- macrophages than in wild-type control cells, it was not abolished, particularly at later timepoints. We therefore explored the hypothesis that the caspase-11 non-canonical inflammasome may contribute to LPS-induced foam cell formation.MethodsMurine J774 macrophages were cultured with LPS delivered extracellularly, or by transfection, in the presence or absence of caspase-11 inhibitors in vitro, and foam cell formation was quantified by microscopy and flow cytometry.ResultsLPS-induced lipid accumulation was independent of exogenous sources of lipid (e.g., serum or LDL), suggesting a prominent role for de novo lipogenesis. Foam cell formation was increased by transfection of LPS into the cytosol of macrophages, in comparison to extracellular delivery. However, both foam cell formation and LDH release (a marker of inflammasome activation) were elevated in response to non-transfected LPS, suggesting that extracellular LPS can both prime and activate caspase-11 at later timepoints (>48 h). Two specific inhibitors of caspase-11, wedelactone and scutellarin, significantly inhibited foam cell formation in response to LPS.ConclusionThe present findings suggest that caspase-11 signaling may contribute to LPS-induced foam cell formation in vitro. Further experiments using caspase-11 knockout macrophages and recombinant inflammasome models are planned to further investigate this hypothesis.Conflict of InterestNone Declared