Lipopolysaccharide augments the uptake of oxidized LDL by up-regulating lectin-like oxidized LDL receptor-1 in macrophages

Abstract

There is a growing body of evidence supporting an intimate association of immune activation with the pathogenesis of cardiovascular diseases, including atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) through scavenging receptors promotes the formation of mature lipid-laden macrophages, which subsequently leads to exacerbation of regional inflammation and atherosclerotic plaque formation. In this study, we first examined changes in the mRNA level of the lectin-like oxLDL receptor-1 (LOX-1) in the mouse macrophage cell line RAW264.7 and the human PMA-induced macrophage cell line THP-1 after LPS stimulation. LPS significantly up-regulated LOX-1 mRNA in RAW264.7 cells; LOX-1 cell-surface protein expression was also increased. Flow cytometry and fluorescence microscopy analyses showed that cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with LPS stimulation. The augmented uptake of Dil-oxLDL was almost completely abrogated by treatment with an anti-LOX-1 antibody. Of note, knockdown of Erk1/2 resulted in a significant reduction of LPS-induced LOX-1 up-regulation. Treatment with U0126, a specific inhibitor of MEK, significantly suppressed LPS-induced expression of LOX-1 at both the mRNA and protein levels. Furthermore, LOX-1 promoter activity was significantly augmented by LPS stimulation; this augmentation was prevented by U0126 treatment. Similar results were also observed in human PMA-induced THP-1 macrophages. Taken together, our results indicate that LPS up-regulates LOX-1, at least in part through activation of the Erk1/2 signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of TLR4-mediated aberrant LOX-1 signaling in the pathogenesis of atherosclerosis.

Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection

“…Dysfunctional HDL that is known to be oxidized [14–17], has previously been shown in vitro to directly influence monocyte [40] and dendritic cell [41] function in systemic inflammatory states [40, 41]. Lipoproteins bind endotoxin which is present in viremic HIV-infected individuals, acts synergistically with LDL ox [42] and may contribute to immune activation [1]. Thus, further studies are needed to elucidate whether oxidized lipoproteins, through effects on immunity and endotoxin, may contribute to immune activation in viremic HIV infected individuals.…”

Relationship among IL-6, LDL cholesterol and lipid peroxidation

“…This receptor is expressed in the aorta of hypertensive, diabetic and hyperlipidemic animals [18], and it is up-regulated in early human atherosclerotic lesions [19]. These results suggest that LOX-1 plays an important role in atherogenesis, by internalizing and degrading ox-LDL, and in inflammatory responses in vivo, raising cellular ox-LDL uptake [20]. The endothelial activation and dysfunction induced by ox-LDL is a key event in the pathogenesis of inflammation and atherosclerosis.…”

Synovial macrophages promote TGF-β signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low-density lipoproteins

“…Interestingly, we could not find significant gene regulation of aggrecanases and did not detect MMP-expression (data not shown), but we previously showed that monocytes can develop a pro-inflammatory phenotype after training by oxLDL 35 . Furthermore, inflammatory factors such as toll-like receptor 4 ligands (e.g., S100A8) could change receptor balances in the synovium, changing affinity of different cell types to take up oxLDL 36 .…”