Toll-like receptor 2 downregulates the cholesterol efflux by activating the nuclear factor‑κB pathway in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis

Li, Yongqiang; Shen, Shuxin; Ding, Shoukun; Wang, Lixia

doi:10.3892/etm.2017.5404

Cited by 13 publications

(9 citation statements)

References 43 publications

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“…Basically, oxLDL is a principle component of endogenous lipid ligand that causes endothelial cell injury, accumulates in macrophage and VSMCs and induces a cellular in ammation response [25,26]. Tlrs were reported to participate in oxLDL induced in ammation response [27][28][29], but an integrated expression feature of Tlrs family in VSMCs under oxLDL stimulation remained unelaborated. In our present study, we found that oxLDL raised the expression of Tlr4 more signi cantly, which was over 1.5-fold than other Tlrs in VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Chen

Xue

Cao

et al. 2020

Preprint

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Background: Oxidized low-density lipoprotein (oxLDL) induced a foam-cell like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptors (Tlrs)-mediated cellular alterations. We previously found that Tlr4 participated in inflammation response in VSMCs under oxLDL stimulation. However, the role of Tlr4 in foam-cell formation and underlying molecular pathways has not been comprehensively elucidated. This study aimed to investigate the role of Tlr4-mediated mechanisms in oxLDL induced foam-cell formation within VSMCs. Methods: After incubated with different dose of oxLDL, the lipid, reactive oxygen species (ROS) accumulation and foam-cell phenotype of the VSMCs were detected. The alteration of Tlr family, ROS and lipid accumulation regulators including the Src kinase, Nox2, Nox4, Mnsod and sirtuins were measured. Then the Tlr4 was knock down and underlying cellular change and altered molecules were detected. Results: We showed that oxLDL induced foam-cell like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. OxLDL induced the strongest upregulation of Tlr4 in the Tlrs family and initiated change of Src activation, Nox2, Mnsod, sirt1 and sirt3 expression. The effect of oxLDL was abolished by Tlr4 knockdown. Furthermore, knocking down of Tlr4 reduced Src activation and led to restored Sirt1/Sirt3 expression. Moreover, inhibiting or knocking down the Src kinase diminished lipid accumulation in VSMCs under oxLDL treatment. And overexpression of Sirt1/3 relieved the oxLDL induced ROS accumulation and foam-cell phenotype in VSMCs.Conclusions: These results demonstrated that Tlr4 is a critical regulator in oxLDL induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in inflammation response of VSMCs, we provide an integrated mechanism about TLR4 in VSMCs phenotype transition under oxLDL stimulation.

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Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Chen

Xue

Cao

et al. 2020

Preprint

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“…Here, toll-like receptors (TLRs) represent PRRs being either present on the PM or within endosomes majorly recognizing nucleic acids ( Latz et al, 2004 ; Nishiya et al, 2005 ; Husebye et al, 2006 ; Johnsen et al, 2006 ; Nilsen et al, 2008 ; Ishii et al, 2014 ; Lester and Li, 2014 ). They share a close relationship with ABCA1-dependent cholesterol removal, which interferes with downstream cascades and vice versa ( Zhu et al, 2008 , 2010 ; Guo et al, 2015 ; Li et al, 2018 ; Ding et al, 2020 ). Similarly, TLR activity seems to decline upon application of statins, inhibitors of cholesterol synthesis ( Mullen et al, 2015 ; Bahrami et al, 2018 ; Venardos et al, 2018 ).…”

Section: Innate Immunitymentioning

confidence: 99%

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Glitscher

Hildt

2021

Front. Physiol.

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Cholesterol has gained tremendous attention as an essential lipid in the life cycle of virtually all viruses. These seem to have developed manifold strategies to modulate the cholesterol metabolism to the side of lipid uptake and de novo synthesis. In turn, affecting the cholesterol homeostasis has emerged as novel broad-spectrum antiviral strategy. On the other hand, the innate immune system is similarly regulated by the lipid and stimulated by its derivatives. This certainly requires attention in the design of antiviral strategies aiming to decrease cellular cholesterol, as evidence accumulates that withdrawal of cholesterol hampers innate immunity. Secondly, there are exceptions to the rule of the abovementioned virus-induced metabolic shift toward cholesterol anabolism. It therefore is of interest to dissect underlying regulatory mechanisms, which we aimed for in this minireview. We further collected evidence for intracellular cholesterol concentrations being less important in viral life cycles as compared to the spatial distribution of the lipid. Various routes of cholesterol trafficking were found to be hijacked in viral infections with respect to organelle-endosome contact sites mediating cholesterol shuttling. Thus, re-distribution of cellular cholesterol in the context of viral infections requires more attention in ongoing research. As a final aim, a pan-antiviral treatment could be found just within the transport and re-adjustment of local cholesterol concentrations. Thus, we aimed to emphasize the importance of the regulatory roles the endosomal system fulfils herein and hope to stimulate research in this field.

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“…A recent study has shown that NF-κB activation may be associated with ABCA1 expression and cholesterol e ux in macrophages [9]. In our study, we found that NF-κB signaling activation inhibitors signi cantly blocked ox-LDL inhibition of ABCA1 expression and increased cholesterol e ux in macrophage-derived foam cells, which suggests that under ox-LDL treatment, NF-κB signal acts as the upstream of ABCA1 and is activated by ox-LDL to inhibit the expression of ABCA1, impeding the reverse cholesterol transport, and aggravating the degree of cell foaming.…”

Section: Discussionmentioning

confidence: 99%

The Key Role of NF-κB Signaling Pathway in Mediating Cholesterol Efflux and Pyroptosis in ox-LDL-induced Macrophages-derived Foam Cells

Liu

et al. 2022

Preprint

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Objective NF-κB plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role in atherosclerosis. Currently, the regulatory mechanism of NF-κB pathway involved in atherosclerosis is not clear.Methods To investigate the role of ox-LDL in NF-κB regulation, the protein expression of phosphorylated NF-κB, a marker of NF-κB pathway activation was measured. The pyroptosis of macrophage was evaluated by western blot and fluorescence microscope. Cholesterol efflux capacity was determined by fluorescence assay and oil red O staining. The inhibitor of activation of NF-κB signal was used to assess the effect of NF-κB signal on macrophage pyroptosis as well as cholesterol efflux in macrophage. Small interfering RNA of ABCA1 was used to assess the effect of ABCA1 on macrophage pyroptosis.Results In this study, we reported THP-1 derived macrophage can be stimulated to increase pyroptosis by ox-LDL in a concentration-dependent. Macrophage pyroptosis was correlated with enhanced activation of NF-κB signal. We found that using inhibitor of NF-κB phosphorylation to attenuate activation of NF-κB signal could decrease macrophage pyroptosis and ox-LDL-induced cholesterol efflux disorder. Furthermore, we found that knocking out of ABCA1 led to increased cell inflammation death. But pyroptosis was blocked, may led to cholesterol efflux dysfunction. Conclusion This study demonstrates that the mechanism of NF-κB involved in the development of atherosclerosis is depending on mediating cell pyroptosis and cholesterol efflux for the first time and provides significant light on macrophage NF-κB signal in atherosclerosis. In addition, ABCA1 may be involved in the development of atherosclerosis as a bridge between cholesterol efflux and pyroptosis in macrophages.

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Toll-like receptor 2 downregulates the cholesterol efflux by activating the nuclear factor‑κB pathway in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis

Cited by 13 publications

References 43 publications

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Endosomal Cholesterol in Viral Infections – A Common Denominator?

The Key Role of NF-κB Signaling Pathway in Mediating Cholesterol Efflux and Pyroptosis in ox-LDL-induced Macrophages-derived Foam Cells

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