Inhibition of LXR Signaling in Human Foam Cells Impairs Macrophage-to-Endothelial Cell Crosstalk and Promotes Endothelial Cell Inflammation

Ultimately, we evaluated macrophage and endothelial cell crosstalk by assessing the impact of macrophage-conditioned supernatants on human endothelial cell. Results: LXR inhibition by GSK2033 resulted in increased levels of cholesterol and oxysterols in human macrophages, alongside notable changes in the cholesterol ester profile. This was accompanied by heightened secretion of pro-inflammatory cytokines such as IL-6 and TNFα, despite a transcriptional repression of IL-1β.

Conditioned media from GSK2033-treated macrophages more effectively activated ICAM-1 and CCL2 expression in endothelial cells. Conclusions/perspectives: Our findings illustrate the intricate relationship between LXR function, cholesterol metabolism, and inflammation in human macrophages. While LXR is required for the proper handling of plaque lipids by macrophages, the differential regulation of IL-1β versus IL-6/TNFα secretion by LXRs could be challenging for potential pharmacological interventions.