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 Retraction in /10.3892/etm.2024.12760

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

doi:10.3892/etm.2017.5404

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

Retraction in: /10.3892/etm.2024.12760

Authors:
- Yongqiang Li
- Shuxin Shen
- Shoukun Ding
- Lixia Wang
View Affiliations

Affiliations: Department of Cardiology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
Published online on: October 31, 2017 https://doi.org/10.3892/etm.2017.5404
Pages: 198-204
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Atherosclerosis is a chronic inflammatory disease, which is triggered by lipid retention. Toll‑like receptor 2 (TLR2) is a novel target for therapeutic intervention in atherosclerosis. In addition, nuclear factor‑κB (NF‑κB) serves important roles in stress response and inflammation. The present study investigated whether TLR2 is involved in the activation of cholesterol efflux in macrophages by regulating the NF‑κB pathway. The human monocytic THP‑1 cell line and murine macrophage RAW264.7 cell line were treated with 50 µg/ml oxidized low‑density lipoprotein (ox‑LDL) for 48 h in order to obtain macrophage foam cells. The cholesterol efflux of the cell lines under exogenous TLR2 treatment was assessed by liquid scintillation counting. Furthermore, the protein and mRNA expression levels of ATP binding cassette transporter A1 (ABCA1), ABCG1 and scavenger receptor B1 (SR‑B1) were examined by western blot and quantitative polymerase chain reaction assays, respectively. To detect the effect of NF‑κB on cholesterol efflux, the cells were divided into three groups, including the control, 10 ng/ml lipopolysaccharides (LPS; 24 h) and 10 ng/ml LPS + 50 µM pyrrolidinedithiocarbamate (PDTC; 24 h) groups. The results indicated that ox‑LDL induced foam cell formation in the THP‑1 and RAW264.7 cells, while TLR2 significantly decreased the cholesterol efflux in dose‑ and time‑dependent manners. Accordingly, TLR2 reduced ABCA1, ABCG1 and SR‑B1 expression at the transcriptional and translational levels in a dose‑dependent manner. In addition, application of PDTC (an NF‑κB specific inhibitor) markedly suppressed the LPS‑induced downregulation of cholesterol efflux. These data revealed that TLR2 may be involved in the activation of cholesterol efflux in macrophages by regulating the NF‑κB signaling pathway.

View Figures

View References

1	Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med. 340:115–126. 1999. View Article : Google Scholar : PubMed/NCBI
2	Falk E, Shah PK and Fuster V: Coronary plaque disruption. Circulation. 92:657–671. 1995. View Article : Google Scholar : PubMed/NCBI
3	Chen S, Xiao J, Liu X, Liu MM, Mo ZC, Yin K, Zhao GJ, Jiang J, Cui LB, Tan CZ, et al: Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells. Acta Pharmacol Sin. 31:1343–1349. 2010. View Article : Google Scholar : PubMed/NCBI
4	Hu C, Dandapat A, Sun L, Chen J, Marwali MR, Romeo F, Sawamura T and Mehta JL: LOX1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high cholesterol diet. Cardiovasc Res. 79:287–293. 2008. View Article : Google Scholar : PubMed/NCBI
5	Karunakaran D, Geoffrion M, Wei L, Gan W, Richards L, Shangari P, DeKemp EM, Beanlands RA, Perisic L, Maegdefessel L, et al: Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv. 2:e16002242016. View Article : Google Scholar : PubMed/NCBI
6	Orekhov AN, Bobryshev YV and Chistiakov DA: The complexity of cell composition of the intima of large arteries: Focus on pericyte-like cells. Cardiovasc Res. 103:438–451. 2014. View Article : Google Scholar : PubMed/NCBI
7	Randolph GJ: Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res. 114:1757–1771. 2014. View Article : Google Scholar : PubMed/NCBI
8	Julve J, Llaverias G, Blancovaca F and Escolàgil JC: Seeking novel targets for improving in vivo macrophage-specific reverse cholesterol transport: Translating basic science into new therapies for the prevention and treatment of atherosclerosis. Curr Vasc Pharmacol. 9:220–237. 2011. View Article : Google Scholar : PubMed/NCBI
9	Hu YW, Wang Q, Ma X, Li XX, Liu XH, Xiao J, Liao DF, Xiang J and Tang CK: TGF-beta1 up-regulates expression of ABCA1, ABCG1 and SR-BI through liver X receptor alpha signaling pathway in THP-1 macrophage-derived foam cells. J Atheroscler Thromb. 17:493–502. 2010. View Article : Google Scholar : PubMed/NCBI
10	Gay NJ and Gangloff M: Structure and function of Toll receptors and their ligands. Annu Rev Biochem. 76:141–165. 2007. View Article : Google Scholar : PubMed/NCBI
11	De Nardo D: Toll-like receptors: Activation, signalling and transcriptional modulation. Cytokine. 74:181–189. 2015. View Article : Google Scholar : PubMed/NCBI
12	Medzhitov R: Toll-like receptors and innate immunity. Nat Rev Immunol. 1:135–145. 2001. View Article : Google Scholar : PubMed/NCBI
13	Hantke K and Braun V: Covalent binding of lipid to protein. Diglyceride and amide-linked fatty acid at the N-terminal end of the murein-lipoprotein of the Escherichia coli outer membrane. Eur J Biochem. 34:284–296. 1973. View Article : Google Scholar : PubMed/NCBI
14	Ozinsky A, Smith KD, Hume D and Underhill DM: Co-operative induction of pro-inflammatory signaling by Toll-like receptors. J Endotoxin Res. 6:393–396. 2000. View Article : Google Scholar : PubMed/NCBI
15	Mercurio F and Manning AM: NF-kappaB as a primary regulator of the stress response. Oncogene. 18:6163–6171. 1999. View Article : Google Scholar : PubMed/NCBI
16	Lawrence T: The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 1:a0016512009. View Article : Google Scholar : PubMed/NCBI
17	Kobayashi H, Hirata M, Saito T, Itoh S, Chung U and Kawaguchi H: Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development. J Biol Chem. 288:28620–28629. 2013. View Article : Google Scholar : PubMed/NCBI
18	Sun Z and Andersson R: NF-kappaB activation and inhibition: A review. Shock. 18:99–106. 2002. View Article : Google Scholar : PubMed/NCBI
19	Vallabhapurapu S and Karin M: Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 27:693–733. 2009. View Article : Google Scholar : PubMed/NCBI
20	Xu S, Huang Y, Xie Y, Lan T, Le K, Chen J, Chen S, Gao S, Xu X, Shen X, et al: Evaluation of foam cell formation in cultured macrophages: An improved method with Oil Red O staining and DiI-oxLDL uptake. Cytotechnology. 62:473–481. 2010. View Article : Google Scholar : PubMed/NCBI
21	Liang B, Wang X, Yan F, Bian YF, Liu M, Bai R, Yang HY, Zhang NN, Yang ZM and Xiao CS: Angiotensin-(1–7) upregulates (ATP-binding cassette transporter A1) ABCA1 expression through cyclic AMP signaling pathway in RAW 264.7 macrophages. Eur Rev Med Pharmacol Sci. 18:985–991. 2014.PubMed/NCBI
22	Mo ZC, Xiao J, Liu XH, Hu YW, Li XX, Yi GH, Wang Z, Tang YL, Liao DF and Tang CK: AOPPs inhibits cholesterol efflux by down-regulating ABCA1 expression in a JAK/STAT signaling pathway-dependent manner. J Atheroscler Thromb. 18:796–807. 2011. View Article : Google Scholar : PubMed/NCBI
23	Liu XY, Lu Q, Ouyang XP, Tang SL, Zhao GJ, Lv YC, He PP, Kuang HJ, Tang YY, Fu Y, et al: Apelin-13 increases expression of ATP-binding cassette transporter A1 via activating protein kinase C α signaling in THP-1 macrophage-derived foam cells. Atherosclerosis. 226:398–407. 2013. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Gao H, Li L, Li L, Gong B, Dong P, Fordjour PA, Zhu Y and Fan G: Danshensu promotes cholesterol efflux in RAW264.7 macrophages. Lipids. 51:1083–1092. 2016. View Article : Google Scholar : PubMed/NCBI
26	Ha T, Liu L, Kelley J, Kao R, Williams D and Li C: Toll-like receptors: New players in myocardial ischemia/reperfusion injury. Antioxid Redox Signal. 15:1875–1893. 2011. View Article : Google Scholar : PubMed/NCBI
27	Yao S, Zong C, Zhang Y, Sang H, Yang M, Jiao P, Fang Y, Yang N, Song G and Qin S: Activating transcription factor 6 mediates oxidized LDL-induced cholesterol accumulation and apoptosis in macrophages by up-regulating CHOP expression. J Atheroscler Thromb. 20:94–107. 2013. View Article : Google Scholar : PubMed/NCBI
28	Pennings M, Meurs I, Ye D, Out R, Hoekstra M, Van Berkel TJ and Van Eck M: Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development. FEBS Lett. 580:5588–5596. 2006. View Article : Google Scholar : PubMed/NCBI
29	Liu X, Ukai T, Yurnoto H, Davey M, Goswami S, Gibson FC III and Genco CA: Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis. 196:146–154. 2008. View Article : Google Scholar : PubMed/NCBI
30	Schoneveld AH, Nijhuis MM Oude, van Middelaar B, Laman JD, de Kleijn DP and Pasterkamp G: Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res. 66:162–169. 2005. View Article : Google Scholar : PubMed/NCBI
31	Mullick AE, Tobias PS and Curtiss LK: Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest. 115:3149–3156. 2005. View Article : Google Scholar : PubMed/NCBI
32	Cao F, Castrillo A, Tontonoz P, Re F and Byrne GI: Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2. Infect Immun. 75:753–759. 2007. View Article : Google Scholar : PubMed/NCBI
33	Zhao GJ, Mo ZC, Tang SL, Ouyang XP, He PP, Lv YC, Yao F, Tan YL, Xie W, Shi JF, et al: Chlamydia pneumoniae negatively regulates ABCA1 expression via TLR2-Nuclear factor-kappa B and miR-33 pathways in THP-1 macrophage-derived foam cells. Atherosclerosis. 235:519–525. 2014. View Article : Google Scholar : PubMed/NCBI
34	Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC and Rothblat GH: The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res. 48:2453–2462. 2007. View Article : Google Scholar : PubMed/NCBI
35	Vaughan AM and Oram JF: ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J Biol Chem. 280:30150–30157. 2005. View Article : Google Scholar : PubMed/NCBI
36	Ji A, Meyer JM, Cai L, Akinmusire A, de Beer MC, Webb NR and van der Westhuyzen DR: Scavenger receptor SR-BI in macrophage lipid metabolism. Atherosclerosis. 217:106–112. 2011. View Article : Google Scholar : PubMed/NCBI
37	Chen S, Sorrentino R, Shimada K, Bulut Y, Doherty TM, Crother TR and Arditi M: Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation. J Immunol. 181:7186–7193. 2008. View Article : Google Scholar : PubMed/NCBI
38	Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA and Neumeier D: Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 97:1715–1722. 1996. View Article : Google Scholar : PubMed/NCBI
39	Janus P, Stokowy T, Jaksik R, Szoltysek K, Handschuh L, Podkowinski J, Widlak W, Kimmel M and Widlak P: Cross talk between cytokine and hyperthermia-induced pathways: Identification of different subsets of NF-κB-dependent genes regulated by TNFα and heat shock. Mol Genet Genomics. 290:1979–1990. 2015. View Article : Google Scholar : PubMed/NCBI
40	Edfeldt K, Swedenborg J, Hansson GK and Yan ZQ: Expression of toll-like receptors in human atherosclerotic lesions: A possible pathway for plaque activation. Circulation. 105:1158–1161. 2002.PubMed/NCBI
41	He C, Lai P, Weng J, Lin S, Wu K, Du X and Liu X: Toll-like receptor 2-mediated NF-κB inflammatory responses in dry eye associated with cGVHD. Mol Vis. 17:2605–2611. 2011.PubMed/NCBI
42	Xavier RJ and Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature. 448:427–434. 2007. View Article : Google Scholar : PubMed/NCBI