Abstract
Electronegative low-density lipoprotein (LDL) (LDL(−)), a modified LDL that is present in blood and exerts atherogenic effects on endothelial cells and monocytes. This study aimed to determine the action of LDL(−) on monocytes differentiated into macrophages. LDL(−) and in vitro-modified LDLs (oxidized, aggregated, and acetylated) were added to macrophages derived from THP1 monocytes over-expressing CD14 (THP1-CD14). Then, cytokine release, cell differentiation, lipid accumulation, and gene expression were measured by ELISA, flow cytometry, thin-layer chromatography, and real-time PCR, respectively. LDL(−) induced more cytokine release in THP1-CD14 macrophages than other modified LDLs. LDL(−) also promoted morphological changes ascribed to differentiated macrophages. The addition of high-density lipoprotein (HDL) and anti-TLR4 counteracted these effects. LDL(−) was highly internalized by macrophages, and it was the major inductor of intracellular lipid accumulation in triglyceride-enriched lipid droplets. In contrast to inflammation, the addition of anti-TLR4 had no effect on lipid accumulation, thus suggesting an uptake pathway alternative to TLR4. In this regard, LDL(−) upregulated the expression of the scavenger receptors CD36 and LOX-1, as well as several genes involved in triglyceride (TG) accumulation. The importance and novelty of the current study is that LDL(−), a physiologically modified LDL, exerted atherogenic effects in macrophages by promoting differentiation, inflammation, and triglyceride-enriched lipid droplets formation in THP1-CD14 macrophages, probably through different receptors.
Highlights
Monocytes and macrophages are essential cells in host defense, as they are part of the mononuclear phagocyte system, and they are involved in both innate and adaptive immune responses
We aimed to investigate the effects of low-density lipoprotein (LDL)(−) on macrophages derived from THP1-CD14 monocytes, which have a similar response to peripheral blood human monocytes in response to LDL(−) [12,25]
At 48 h, this difference remained similar for the interleukins, but it increased for granulocyte-macrophage colony-stimulating factor (GM-CSF)
Summary
Monocytes and macrophages are essential cells in host defense, as they are part of the mononuclear phagocyte system, and they are involved in both innate and adaptive immune responses. During the early stages of atherosclerosis, a recruitment of monocytes towards inflammation areas occurs. Once in the vessel wall, monocytes differentiate into macrophages, which actively provide a pro-inflammatory microenvironment and contribute to remove extracellular lipids. Accumulation of LDs gives to macrophages a foamy appearance as they become lipid-laden foam cells, a hallmark of atherosclerosis and an essential element in plaque development [1,2]. Modified LDLs are inductors of proinflammatory macrophage polarization, and they are abundant in atherosclerotic lesion areas [1,5]. LDL(−) has higher phospholipolytic activities, higher aggregation levels, and higher proteoglycan binding than native LDL
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