The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

Michael, Daryn R.; Davies, Teifion; Laubertová, Lucia; Gallagher, Hayley; Ramji, Dipak Purshottam

doi:10.1007/s11745-015-3993-0

Cited by 14 publications

(8 citation statements)

References 31 publications

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“…Although we found that PI3K participates in the phagocytosis of S. typhimurium, we wanted to determine how PI3K influences the phagocytosis of S. typhimurium. Several studies have shown that inhibition of PI3K reduces the expression of scavenger receptors [29] and suppresses the adhesion of monocytes/macrophages [30]. Our data show that inhibition of PI3K by LY294002 not only reduced the expression of scavenger receptors, but also suppressed the adhesion of the cells.…”

Section: Discussionsupporting

confidence: 56%

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Overexpression of Toll-Like Receptor 4 Contributes to Phagocytosis of Salmonella Enterica Serovar Typhimurium via Phosphoinositide 3-Kinase Signaling in Sheep

Wang

Deng

Cao

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phagocytosis of bacteria by monocytes/macrophages can trigger the immune response and the clearance of bacteria. This innate immune response involves Toll-like receptor 4 (TLR4). However, much remains unknown about the mechanism of TLR4-regulated phagocytosis of Salmonella enterica serovar Typhimurium (S. typhimurium) within sheep monocytes/macrophages. Here, we aimed to address these knowledge gaps by infecting transgenic sheep overexpressing TLR4 with S. typhimurium and examining the phagocytic mechanisms involved. Methods: Transgenic sheep were generated by microinjection of the constructed plasmids into fertilized eggs. Monocytes/macrophages isolated from sheep blood were stimulated with LPS and S. typhimurium. Phagocytosis-related factor expression, phagocytic ability, and adhesion were then determined. TLR4/phosphatidylinositide 3-kinase (PI3K) signaling was inhibited to investigate if this pathway is involved in changes in bacterial internalization in sheep. Results: We found that TLR4 overexpression effectively activated the PI3K signaling pathway and upregulated the expression of scavenger receptors. Additionally, actin polymerization and adhesive capacity were both enhanced in TLR4-overexpressing sheep monocytes/macrophages. TLR4 inhibition decreased S. typhimurium phagocytosis by reducing the actin polymerization and adhesive capacity of cells. Furthermore, inhibition of PI3K markedly impaired TLR4-dependent phagocytosis by restraining actin polymerization and scavenger receptor expression and reduced the adhesive capacity of the monocytes/macrophages. Conclusion: Our findings indicate that overexpression of TLR4 enhances phagocytosis through PI3K signaling and the subsequent activation of actin polymerization and scavenger receptors in sheep monocytes/macrophages infected with S. typhimurium.

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Section: Discussionsupporting

confidence: 56%

“…Furthermore, CD36 has been implicated in actin cytoskeleton rearrangement [28]. Inhibition of PI3K can decrease the expression of scavenger receptors [29] and influence scavenger receptor-mediated cell adhesion [30]. These results suggest the possible interactions among TLR4, scavenger receptors, and PI3K during bacterial internalization.…”

Section: Introductionmentioning

confidence: 96%

Overexpression of Toll-Like Receptor 4 Contributes to Phagocytosis of Salmonella Enterica Serovar Typhimurium via Phosphoinositide 3-Kinase Signaling in Sheep

Wang

Deng

Cao

et al. 2018

Cell Physiol Biochem

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“…These findings showed that Rab5 played an important role in the maturation of foam cells. Previous study demonstrated the critical role of PI3K signaling played in the uptake of modified LDL via its up-regulation effect on SRs, which in turn affects the maturation of foam cells [ 21 ]. Based on the analysis mentioned as above, the formation of foam cells may be driven by the association of Rab5 with PI3K pathway.…”

Section: Discussionmentioning

confidence: 99%

Role of Rab5 in the formation of macrophage-derived foam cell

et al. 2017

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BackgroundFoam cells play a key role in the occurrence and pathogenesis of atherosclerosis. Its formation starts with the ingestion of oxidized low-density lipoprotein (oxLDL). The process is associated with Ras related protein in brain 5 (Rab5) which plays a critical role in regulating endocytosis and early endosomal trafficking. Base on this, we presumed that Rab5 might participate in the maturation of foam cell. The aim of this study is to investigate the effect of Rab5 on macrophage cholesterol during the evolvement of macrophage when induced by oxLDL to the formation of foam cell.MethodsImmunohistochemistry was performed to analyze the distribution of macrophages and Rab5 in atherosclerotic plaque. RNA inteference study and transfection of inactive mutant (GFP-Rab5-S34N) and active mutant (GFP-Rab5-Q79L) in U937-derived macrophage were utilized to investigate the impact of Rab5 on the process of macrophage cholesterol, which could be detected by oil red O staining, determination of intracellular lipid content, filipin staining, nile red staining and the costaining of early endosome antigen-1 (EEA-1) and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylin dicarbocyanine (Dil)-labelled oxLDL (Dil-oxLDL).ResultsRab5 was found abundantly localized in macrophage rich areas of human atherosclerotic lesions. On the foam cell study, the expression of Rab5 was increased after the incubation of oxLDL. The inteference study indicated the depletion of Rab5 led to the decreases of oil red O staining areas, total cholesterol and cholesterol esters in U937-derived marophages. Moreover, the fluorescence intensity of filipin and nile red staining were lower in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L. The confocal study demonstrated less Dil-oxLDL was internalized in GFP-Rab5-S34N as compared with GFP-Rab5-Q79L; the result showed also the decrease in colocalization of internalized Dil-oxLDL and EEA-1 for GFP-Rab5-S34N as compared with GFP-Rab5-Q79L.ConclusionsRab5 plays an important role in modulating the intracellular cholesterol of macrophages and consequently mediating the formation of foam cells.

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“…transcytosis-related proteins; and attenuate atherosclerosis (Gareus et al 2008;Zhang et al 2014). The suppression of PI3K is also reported to attenuate the uptake of LDL (Michael et al 2015). Through the regulation of NF-B and PI3K-AKT signaling pathways, shikonin inhibits the growth (Shi and Cao 2014;Wang et al 2014b;Tian et al 2015), invasion, and metastasis (Min et al 2011;Chen et al 2014) of cells, although most studies are performed in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

Zhang

et al. 2015

Can. J. Physiol. Pharmacol.

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Shikonin is a naphthoquinone compound extracted from the Chinese herb purple gromwell. Shikonin has broad antibacterial, anti-inflammatory, and antitumor activities. The tumor necrosis factor-α (TNF-α)-induced proliferation and invasion of vascular smooth muscle cells (VSMCs) is an important factor that contributes to atherosclerosis. The effects of shikonin on the proliferation and apoptosis of VSMCs have been reported; however, the function of shikonin on TNF-α-mediated growth and invasion of VSMCs during atherosclerosis remains unclear. In this study, we used Western blot, flow cytometry, real-time quantitative PCR, and enzyme-linked immunosorbent assay to investigate the effect of shikonin on the TNF-α-induced growth and invasion of VSMCs and to determine the underlying mechanism. Our results showed that shikonin inhibits the TNF-α-mediated growth and invasion. Further study revealed that shikonin regulates the activation of nuclear factor kappa B and phosphatidyl inositol 3-kinase signaling pathways; modulates the expression of cyclin D1, cyclin E, B-cell lymphoma 2, and Bax; activates caspase-3 and caspase-9; induces cell cycle arrest; and promotes the apoptosis of VSMCs. Together, our results indicate that shikonin may become a promising agent for the treatment of atherosclerosis and they also establish foundation for the development of anti-atherosclerosis drugs.

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The Phosphoinositide 3‐Kinase Signaling Pathway is Involved in the Control of Modified Low‐Density Lipoprotein Uptake by Human Macrophages

Cited by 14 publications

References 31 publications

Overexpression of Toll-Like Receptor 4 Contributes to Phagocytosis of Salmonella Enterica Serovar Typhimurium via Phosphoinositide 3-Kinase Signaling in Sheep

Overexpression of Toll-Like Receptor 4 Contributes to Phagocytosis of Salmonella Enterica Serovar Typhimurium via Phosphoinositide 3-Kinase Signaling in Sheep

Role of Rab5 in the formation of macrophage-derived foam cell

Shikonin inhibits TNF-α-induced growth and invasion of rat aortic vascular smooth muscle cells

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