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. 2024 Jun 20;25(12):6808.
doi: 10.3390/ijms25126808.

Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation

Jaemi Kim  1 , Ji-Yun Kim  2 , Hye-Eun Byeon  2 , Ji-Won Kim  1 , Hyoun-Ah Kim  1 , Chang-Hee Suh  1 , Sangdun Choi  3 , MacRae F Linton  4   5 , Ju-Yang Jung  1
Affiliations

Inhibition of Toll-like Receptors Alters Macrophage Cholesterol Efflux and Foam Cell Formation

Jaemi Kim et al. Int J Mol Sci. .

Abstract

Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

Keywords: atherosclerosis; cholesterol efflux; foam cells; toll-like receptor.

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Conflict of interest statement

The authors have no relevant financial or non-financial interest to disclose.

Figures

Figure 1
Figure 1
Changes in foam cell formation and cholesterol levels in stimulated THP-1 cells with LPS and oxidized LDL after MIP2 treatment. (A,B). Oil red-O stainings show Foam cells are increased in stimulated THP-1 cells with LPS and LPS + oxidized LDL, and decreased in those after administration of MIP2 10, 20, and 30 μM (* p < 0.001). (C) Amount of total cholesterol is increased in stimulated THP-1 cells with LPS + oxidized LDL and those after administration of MIP2 10 μM and decreased in those after administration of 20 and 30 μM MIP2 (* p < 0.001). Amount of free cholesterol is increased in stimulated THP-1 cells with LPS + oxidized LDL and decreased in those after administration of MIP2 10, 20, and 30 μM (* p < 0.001).
Figure 2
Figure 2
Changes in cholesterol efflux-associated receptors in stimulated THP-1 cells with LPS and oxidized LDL after MIP2 treatment. (A,B). WB results show that expressions of ABCA1 and ABCG1 do not differ in stimulated THP-1 cells with LPS + oxidized LDL after administration of 10, 20 and 30 μM MIP2 (* p < 0.001), expressions of SR-B1 and LXRα are increased in those after administration of 20 and 30 μM MIP2 (* p < 0.001), and expressions of PPARγ are increased in those after administration of MIP2 10, 20, and 30 μM (* p < 0.001). (C) RT-PCR results show that mRNA levels of ABCA1 are increased in the stimulated THP-1 cells with LPS + oxidized LDL after the administration of MIP2 30 μM (* p < 0.001), mRNA levels of ABCG1 are increased in the stimulated THP-1 cells with LPS + oxidized LDL after administration of 20 and 30 μM MIP2 (* p < 0.001), and mRNA expressions of SR-B1, LXRα, and PPARγ are increased in the stimulated THP-1 cells with LPS + oxidized LDL after administration of MIP2 10, 20, and 30 μM (* p < 0.001).
Figure 3
Figure 3
Changes in cytokines levels in stimulated THP-1 cells with LPS and oxidized LDL after MIP2 treatment. Concentrations of IL-1β, TNF-α, IL-6, and IL-10 were decreased in the stimulated THP-1 cells with LPS and oxidized LDL after the administration of 10, 20 and 30 μM MIP2 (* p < 0.001).
Figure 4
Figure 4
Changes in phosphorylation of MAP kinases in stimulated THP-1 cells with LPS and oxidized LDL after MIP2 treatment. (A,B). WB results show that expressions of phosphorylated p65, p38, and JNK are decreased in stimulated THP-1 cells with LPS and oxidized LDL after administration of 10, 20 and 30 μM MIP2 (* p < 0.001). (C,D) WB results show that expressions of ABCA1, ABCG1, SR-B1, LXRα and PPARγ are increased in stimulated THP-1 cells with LPS and oxidized LDL after BAY treatment (* p < 0.001).
Figure 5
Figure 5
Changes in reactive oxygen species (ROS) production in stimulated THP-1 cells with LPS and oxidized LDL after MIP2 treatment. Amount of ROS production are decreased in stimulated THP-1 cells with LPS + oxidized LDL after administration of 20 and 30 μM MIP2 (* p < 0.001).
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References

    1. Linton M.F., Yancey P.G., Davies S.S., Jerome W.G., Linton E.F., Song W.L., Doran A.C., Vickers K.C. The Role of Lipids and Lipoproteins in Atherosclerosis. In: Feingold K.R., Anawalt B., Boyce A., editors. Endotext. MDText.com, Inc.; South Dartmouth, MA, USA: 2000.
    1. Berenice Martinez-Shio E., Martin Cardenas-Hernandez A., Jimenez-Suarez V., Marín-Jáuregui L.S., del Campo C.C.-M., González-Amaro R., Escobedo-Uribe C.D., Monsiváis-Urenda A.E. Differentiation of circulating monocytes into macrophages with metabolically activated phenotype regulates inflammation in dyslipidemia patients. Clin. Exp. Immunol. 2022;208:83–94. doi: 10.1093/cei/uxac013. - DOI - PMC - PubMed
    1. Xie Y., Chen H., Qu P., Qiao X., Guo L., Liu L. Novel insight on the role of Macrophages in atherosclerosis: Focus on polarization, apoptosis and efferocytosis. Int. Immunopharmacol. 2022;113:109260. doi: 10.1016/j.intimp.2022.109260. - DOI - PubMed
    1. Boren J., Chapman M.J., Krauss R.M., Packard C.J., Bentzon J.F., Binder C.J., Daemen M.J., Demer L.L., Hegele R.A., Nicholls S.J., et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: Pathophysiological, genetic, and therapeutic insights: A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 2020;41:2313–2330. doi: 10.1093/eurheartj/ehz962. - DOI - PMC - PubMed
    1. Pownall H.J., Rosales C., Gillard B.K., Gotto A.M., Jr. High-density lipoproteins, reverse cholesterol transport and atherogenesis. Nat. Rev. Cardiol. 2021;18:712–723. doi: 10.1038/s41569-021-00538-z. - DOI - PubMed

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