A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages

Gu, Jianqiu; Wang, Di-Fei; Yan, Xiangqiao; Zhong, Wei-Li; Zhang, Jin; Fan, Bin; Ikuyama, Shoichiro

doi:10.1152/ajpendo.00159.2010

Cited by 35 publications

(17 citation statements)

References 40 publications

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“…The use of antagonist showed a clear reduction in lipid uptake, and thus foam cell formation indicated less intracellular Oil Red O staining in the fixed macrophages ( Figure 6B-6E). TLR9 activation and blockade in the presence of LDL gave the same results, and was described previously 27,28 (data not shown). Foam cells, formed by oxidized LDL (oxLDL) uptake of macrophages, die of releasing lipids, intracellular molecules, and necrotic debris which can further activate the remaining macrophages via endosomal receptors like TLR7/ TLR9.…”

Section: Tlr7/9 Blockade Reduced Foam Cell Formation By Macrophagessupporting

confidence: 87%

“…38 TLR9 was previously described to be involved in foam cell formation via upregulation of nicotinamide adenine dinucleotide phosphate oxidase 1, lectin-type oxLDL receptor 1, and perilipin 3. 27,28 This foam cell formation was nuclear factor-kappaB-and IFN regulatory factor 7-dependent, and can be countered via liver X receptor activation. 37 Both nuclear factor-kappaB and IFN regulatory factor 7 are also important mediators of TLR7 signaling, and additionally we show that TLR7 stimulation in the presence of LDL leads to lipid uptake in macrophages.…”

Section: E78 Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

“…27,28,36,37 Both TLR7 and TLR9 agonists cause upregulation of adipocyte differentiationrelated protein that is involved in lipid droplet formation in macrophages. 38 TLR9 was previously described to be involved in foam cell formation via upregulation of nicotinamide adenine dinucleotide phosphate oxidase 1, lectin-type oxLDL receptor 1, and perilipin 3.…”

Section: E78 Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

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Blocking Toll-Like Receptors 7 and 9 Reduces Postinterventional Remodeling via Reduced Macrophage Activation, Foam Cell Formation, and Migration

Karper

Ewing

Habets

et al. 2012

ATVB

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e72P ostinterventional remodeling is a critical determinant of long-term efficacy of percutaneous coronary interventions. Restenosis is characterized by acute elastic recoil and intimal hyperplasia attributable to inflammation, smooth muscle cell (SMC) proliferation, and extracellular matrix turnover. 1 Under hypercholesterolemic conditions, this is accompanied by influx and accumulation of low-density lipoprotein (LDL) cholesterol in the vessel wall that becomes oxidized and taken up by macrophages. Thereby these macrophages become foam cells and initiate a process of accelerated atherosclerosis.2 Previously, we and others described an important causal role for extracellular toll-like receptors (TLRs) in postinterventional remodeling. It has been shown that TLR4 and the MyD88-dependent pathway play an important role in restenosis and postinterventional accelerated atherosclerosis. [3][4][5][6] Similarly, a crucial role for TLR2 has been described. TLRs, as part of the innate immune system, are pattern recognition receptors known to recognize exogenous ligands that originate from bacteria or viruses as well as endogenous ligands. These endogenous ligands may be released after tissue damage or cell stress, processes that may be initiated by percutaneous coronary interventions. MyD88-dependent signaling is the dominant activation pathway of TLR signaling leading to nuclear factor-kappaB activation and upregulation of several proinflammatory cytokines. Because TLR2 and TLR4 are known to be expressed on the cell surface of vascular cells and activated in vascular disease processes via damageassociated molecular patterns as endogenous ligands, such as heat shock proteins, fibronectin containing extradomain A, tenascin-C, and high-mobility group box 1 (HMGB1), [8][9][10][11] research in the cardiovascular field mainly focused on TLR2 and TLR4. Objective-The role of toll-like receptors (TLRs) in vascular remodeling is well established. However, the involvement of the endosomal TLRs is unknown. Here, we study the effect of combined blocking of TLR7 and TLR9 on postinterventional remodeling and accelerated atherosclerosis. Methods and Results-In hypercholesterolemic apolipoprotein E*3-Leiden mice, femoral artery cuff placement led to strong increase of TLR7 and TLR9 presence demonstrated by immunohistochemistry. Blocking TLR7/9 with a dual antagonist in vivo reduced neointimal thickening and foam cell accumulation 14 days after surgery by 65.6% (P=0.0079). Intima/media ratio was reduced by 64.5% and luminal stenosis by 62.8%. The TLR7/9 antagonist reduced the arterial wall inflammation, with reduced macrophage infiltration, decreased cytoplasmic high-mobility group box 1 expression, and altered serum interleukin-10 levels. Stimulation of cultured macrophages with TLR7 and TLR9 ligands enhanced tumor necrosis factor-α expression, which is decreased by TLR7/9 antagonist coadministration. Additionally, the antagonist abolished the TLR7/9-enhanced low-density lipoprotein uptake. The antagonist also reduced oxidized lowden...

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Section: Tlr7/9 Blockade Reduced Foam Cell Formation By Macrophagessupporting

confidence: 87%

Section: E78 Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Section: E78 Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

See 1 more Smart Citation

Blocking Toll-Like Receptors 7 and 9 Reduces Postinterventional Remodeling via Reduced Macrophage Activation, Foam Cell Formation, and Migration

Karper

Ewing

Habets

et al. 2012

ATVB

View full text Add to dashboard Cite

show abstract

“…In vitro data describing CpG DNA-mediated activation of macrophages stimulating foam cell formation 16,29,30 imply that TLR9 might rather contribute to the development of atherosclerosis. However, in contrast to this, our in vivo studies demonstrate that TLR9 has a protective role against atherosclerosis in the ApoE −/− mouse model.…”

Section: Discussionmentioning

confidence: 99%

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

Koulis

Chen

Hausding

et al. 2014

ATVB

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Objective— Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E–deficient (ApoE −/− ) mice. Approach and Results— Newly generated double-knockout ApoE −/− :TLR9 −/− mice and control ApoE −/− mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE −/− :TLR9 −/− mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 + T cells. Although ApoE −/− :TLR9 −/− mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE −/− :TLR9 −/− mice, CD4 + T-cell accumulation was further investigated and depletion of these cells in ApoE −/− :TLR9 −/− mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE −/− mice resulted in a reduction of lesion severity. Conclusions— Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE −/− mice fed a high-fat diet. CD4 + T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.

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“…TIP47 is also involved in lipid droplet formation (Bulankina et al, 2009). In particular, activation of TLR9 in macrophages enhances TIP47 expression and promotes lipid accumulation (Gu et al, 2010). Finally, TIP47 has been shown to protect mitochondrial integrity and limit stressinduced cell death (Hocsak et al, 2010a,b).…”

Section: Introductionmentioning

confidence: 99%

The cellular protein TIP47 restricts Respirovirus multiplication leading to decreased virus particle production

et al. 2013

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a b s t r a c tThe cellular tail-interacting 47-kDa protein (TIP47) acts positively on HIV-1 and vaccinia virus production. We show here that TIP47, in contrast, acts as a restriction factor for Sendai virus production. This conclusion is supported by the occurrence of increased or decreased virus production upon its suppression or overexpression, respectively. Pulse-chase metabolic labeling of viral proteins under conditions of TIP47 suppression reveals an increased rate of viral protein synthesis followed by increased incorporation of viral proteins into virus particles. TIP47 is here described for the first time as a viral restriction factor that acts by limiting viral protein synthesis.

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A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages

Abstract: A Toll-like receptor 9-mediated pathway stimulates perilipin 3 (TIP47) expression and induces lipid accumulation in macrophages.

Cited by 35 publications

References 40 publications

Blocking Toll-Like Receptors 7 and 9 Reduces Postinterventional Remodeling via Reduced Macrophage Activation, Foam Cell Formation, and Migration

Blocking Toll-Like Receptors 7 and 9 Reduces Postinterventional Remodeling via Reduced Macrophage Activation, Foam Cell Formation, and Migration

Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice

The cellular protein TIP47 restricts Respirovirus multiplication leading to decreased virus particle production

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