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

ABSTRACT: Backgrounds: During atherogenesis, macrophages turn into foam cells by engulfing lipids present within the atheroma plaques. The shift of foam cells towardspro- or anti-inflammatory phenotypes, critical step in disease progression, is still poorly understood. Liver X Receptors (LXRs) play a pivotal role in the macrophage response to lipid, promoting the expression of key genes of cholesterol efflux, mitigating intracellular cholesterol accumulation. LXRs also exert balanced actions on inflammation in human macrophages, displaying both pro- and anti-inflammatory effects. Aims and methods: Our study explored the role of LXRs in the functional response of human macrophage to lipid-rich plaque environment. We used primary human macrophages treated with atheroma plaque extracts and assessed the impact of pharmacological LXR inhibition by GSK2033 on cholesterol homeostasis and inflammatory response. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292423 | GEO | 2026/03/19

REPOSITORIES: GEO

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Project description:The objective of the study was to figure out the impact of LXR signaling on human macrophages. Primary human macrophages in an early differentiating and a mature differentiation state were treated with the LXR agonist T091317 for 4 and 24 h and transcriptome-wide expression analysis were performed. As LXRa is highly induced during macrophage differentiation and 68% of all LXRs targets change their expression during this process, we suggest that LXRs have essential functions in macrophage development. More than 238 genes are regulated in early as well as mature macrophages by activation of LXRs; most of them are up-regulated. LXRs administrate differentiation state specific as well as common macrophages functions related primarily to lipid homeostasis, immune response and cell fate. Interestingly, almost only genes related to lipid and cholesterol metabolism are overrepresented among early induced genes, whereas genes related to immune functions respond later, implying the existence of indirect mechanisms of control. Furthermore, in early differentiating macrophages cell proliferation and cell death associated genes are induced after 24 h of LXR activation, whereas in mature macrophages, showing high LXRa expression, the same functional cluster respond far earlier (4 h) after LXR ligand treatment. In conclusion, our data suggest that LXRs are modulators of macrophage differentiation, operating principally as positive transcriptional regulators of genes involved in lipid and cholesterol metabolism and by this indirectly influencing the immunophenotype of macrophages. CD14 positive cells of healthy donors were isolated by magnetic separation and differentiated in the presence of human serum to macrophages. At an early differentiating state (16 h after isolation) and at in mature differentiating state (day 11 after isolation) the cells were treated with the synthetical LXR agonist T091317 respective its solvent DMSO for 4 and 24 h. RNA was isolated and a whole genome microarray was performed.

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

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