Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis

Liu, Cong-Lin; Santos, Marcela M.; Fernandes, Cleverson Rodrigues; Liao, Mengyang; Iamarene, Karine; Zhang, Jinying; Sukhova, Galina K.; Shi, Guo‐Ping

doi:10.1038/s41598-017-00977-0

Cited by 21 publications

(16 citation statements)

References 90 publications

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“…16) In contrast, Liu, et al demonstrated a detrimental role for TLR7 in diet-induced atherosclerosis in ApoE −/− mice by showing an increase in lesion inflammation (MHC-II), lesion proinflammatory cytokine expression (IL-6), lesion protease expression (CatS and MMP-9), and systemic inflammation (plasma). 6) In agreement with these findings, we show that the pro-inflammatory stimulation of TLR7 by high concentrations of R848 impairs reendothelialization following acute vascular injury combined with increased levels of EMPs, induced Sca1/Flk1 positive cells, and elevated levels of IL-6 and RANTES. TLR7 activation in WT mice induced a systemic inflammatory reaction and disturbed the regeneration of endothelial cells after injury.…”

Section: Discussionsupporting

confidence: 89%

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Toll-Like Receptor 7 Stimulation Promotes the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

et al. 2020

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Atherosclerosis is a chronic inflammatory disease with multiple characteristic facets, including vascular inflammation, endothelial dysfunction, plaque development, impaired blood flow, and cholesterol deposition through dyslipidemia. Toll-like receptors (TLRs) of the innate immune system have been closely linked to the development of atherosclerotic lesions. TLR7 recognizes viral or endogenous single-stranded RNA, which is released during vascular apoptosis and necrosis. The role of TLR7 in vascular disease remains controversial, and therefore, we sought to investigate the effects of TLR7 stimulation in mice. Intravenous injection of a ligand for TLR7 (R848) induced a significant pro-inflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid artery, as measured by Evan's blue staining, and increased numbers of circulating endothelial microparticles (EMPs) and circulating Sca1/Flk1 positive cells as a marker for increased endothelial damage. Chronic subcutaneous stimulation of TLR7 in apolipoprotein E-deficient (ApoE −/−) mice increased aortic production of reactive oxygen species (ROS), the number of circulating EMPs, and most importantly, augmented the formation of atherosclerotic plaque when compared with vehicle-treated animals. Systemic stimulation of TLR7 leads to impaired reendothelialization upon acute vascular injury and is associated with the production of pro-inflammatory cytokines and increased levels of circulating EMPs and Sca1/ Flk1 positive cells. Importantly, ApoE −/− mice chronically treated with R848 displayed increased atherosclerotic plaque development and elevated levels of ROS in the aortic tissue. In addition, TLR7-activation-induced apoptosis and impaired migration in human coronary artery endothelial cells and showed significant upregulation of the signaling cascade of IL-1 receptor-associated kinase (IRAK) 2 and IRAK4. Our data highlight the importance of fully understanding the pathomechanisms involved in atherogenesis, and further studies are necessary to identify the ligand-specific effects of TLR7 for possible therapeutic targeting.

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Section: Discussionsupporting

confidence: 89%

“…Recently, Liu, et al demonstrated a pro-inflammatory role for TLR7 in atherogenic diet-induced atherosclerosis in apolipoprotein E-deficient (ApoE −/− ) mice. 6) To further investigate the role of TLR7 in atherosclerosis, we stimulated TLR7 using the R848 ligand in vitro, as well as in acute and chronic vascular injury experiments in vivo.…”

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confidence: 99%

Toll-Like Receptor 7 Stimulation Promotes the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

et al. 2020

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“…Chronic dysregulated TLR activation has been reported in a plethora of non-infectious pathologies and autoimmune diseases, including CVD [84,85], atherosclerosis [86,87], and type-2 diabetes [88,89]. As demonstrated by animal TLR knockout models [90][91][92][93][94][95][96] and studies involving TLR deficiency [97,98] and polymorphisms in humans [99][100][101][102][103][104][105][106][107][108][109][110][111], absence or improper function of TLRs can attenuate inflammation, influence disease susceptibility, and restore homeostatic balance. Thus, TLRs have become targets of TLR inhibition therapies [112][113][114][115][116].…”

Section: Taurine Toll-like Receptors and Cardiovascular Diseasementioning

confidence: 99%

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease

et al. 2020

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Taurine is a non-protein amino acid that is expressed in the majority of animal tissues. With its unique sulfonic acid makeup, taurine influences cellular functions, including osmoregulation, antioxidation, ion movement modulation, and conjugation of bile acids. Taurine exerts anti-inflammatory effects that improve diabetes and has shown benefits to the cardiovascular system, possibly by inhibition of the renin angiotensin system. The beneficial effects of taurine are reviewed.

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“…The first study reported from Salagianni et al showed a protective effect for TLR7 in atherosclerosis through a macrophage shift towards a repair-healing subtype [9]. In contrast, Liu et al indicated that TLR7 has a detrimental role [24]. The discrepancy in these two studies might be explained by the use of different diet.…”

Section: Discussionmentioning

confidence: 99%

Treatment with a Toll‐like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice

et al. 2020

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Background The interplay between innate and adaptive immunity is central in life‐threatening clinical complications of atherosclerosis such as myocardial infarction and stroke. The specific mechanisms involved and their protective versus detrimental effects in the disease process remain poorly understood. We have previously shown that higher levels of Toll‐like receptor 7 (TLR7) expression in human atherosclerotic lesions are correlated with better patient outcome. Objective In this study, we explored whether TLR7 activation can ameliorate disease in experimental atherosclerosis in mice. Methods Apolipoprotein E deficient mice (Apoe−/−) with established disease were injected for five weeks intraperitoneally with the TLR7 ligand R848. Local effects were evaluated by characterization of the lesion. Systemic effects of the treatment were investigated by immune composition analysis in the spleen and plasma measurements. Results The in vivo treatment arrested lesion progression in the aorta. We also detected expansion of marginal zone B cells and Treg in the spleen together with increased plasma IgM antibodies against oxidized low‐density lipoprotein (oxLDL) and reduced plasma cholesterol levels. These changes were accompanied by increased accumulation of IgM antibodies, decreased necrosis and fewer apoptotic cells in atherosclerotic lesions. Conclusions Our findings show that TLR7 stimulation could ameliorate atherosclerotic lesion burden and reduce plasma cholesterol in Apoe−/− mice. TLR7 stimulation was associated with an atheroprotective B‐cell and Treg response, which may have systemic and local effects within lesions that could prevent arterial lipid accumulation and inflammation.

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Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis

Cited by 21 publications

References 90 publications

Toll-Like Receptor 7 Stimulation Promotes the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

Toll-Like Receptor 7 Stimulation Promotes the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice

The Anti-Inflammatory Effect of Taurine on Cardiovascular Disease

Treatment with a Toll‐like Receptor 7 ligand evokes protective immunity against atherosclerosis in hypercholesterolaemic mice

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