Toll样受体与动脉粥样硬化

动脉粥样硬化作为一种炎症性疾病,研究表明感染因子与动脉粥样硬化的发生与发展有关。Toll样受体是天然免疫系统识别病原微生物的主要受体．在天然免疫反应中具有重要的作用,近年来研究认为Toll样受体之一Toll样受体4与动脉粥样硬化的发生发展密切相关．其可能成为动脉粥样硬化防治的标靶．本文主要对Toll样受体4在动脉粥样硬化的发生发展中的作用作一综述．     

Toll样受体4在动脉粥样硬化中的作用研究进展

Toll样受体尤其是Toll样受体4作为介导天然免疫反应的一类跨膜受体蛋白在动脉粥样硬化进程中的作用日益引起关注,本文就其结构、配体及其在动脉粥样硬化各阶段作用及动脉粥样硬化免疫学治疗现状作一概述。     

Toll样受体4与肝损伤

Toll样受体是近几年发现的天然免疫受体，主要参与病原微生物产物的识别及炎症信号传导，是天然免疫与获得性免疫的连接点。Toll样受体4介导内毒素引起的感染性免疫反应，参与了肝脏内的损伤、纤维化、再生与修复等炎症反应过程。     

Toll样受体4／核因子-κB信号途径在冠心病中的研究进展

Toll样受体是天然免疫系统识别病原微生物的主要受体，在天然免疫反应中具有重要作用。近年研究Toll样受体之一Toll样受体4及其介导的信号转导途径与冠心病的发生发展密切相关。     

Toll样受体4与肝损伤

Toll样受体是近几年发现的天然免疫受体,主要参与病原微生物产物的识别及炎症信号传导,是天然免疫与获得性免疫的连接点。Toll样受体4介导内毒素引起的感染性免疫反应,参与了肝脏内的损伤、纤维化、再生与修复等炎症反应过程。     

TLR2/4-IRF3信号通路调控胆固醇逆转运及其对动脉粥样硬化影响的研究进展

Toll样受体（toll like receptors,TLRs）是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要的作用,TLR2／4-IRF3信号通路对胆固醇逆转运的调控能对动脉粥样硬化易损斑块产生影响。本文就TLR2／4-IRF3信号通路如何调控胆固醇逆转运从而影响动脉粥样硬化的发生发展作一综述。     

Toll样受体在结核分枝杆菌致病机制中的作用研究进展

结核分枝杆菌是肺结核的致病菌,它可寄生在细胞内并长期存活.目前结核杆菌的致病机制及机体对其的免疫反应尚未完全阐明.Toll样受体属于模式识别受体,在结核杆菌宿主防御反应中具有极为重要的作用.Toll样受体作为连接天然免疫与获得性免疫的"桥梁",在机体免疫调节中的作用已愈来愈受关注.关于Toll样受体与结核杆菌的相关研究已成为生命科学领域的热点.     

Toll样受体4与缺血性脑损伤

Toll样受体是天然免疫系统识别病原微生物的主要受体,在天然免疫反应中具有重要作用。Toll样受体4(TLR4)不仅是介导脂多糖信号跨膜转导的主要受体,而且也参与了缺血性损伤等非病原微生物性炎症反应。有关TLR4及其介导的信号转导在脑血管病中的作用日益引起人们的关注。深入研究TLR4在脑血管病中的作用,有可能为进一步揭示脑血管病的发病机制并为寻求有效的防治措施提供重要的理论基础。     

Toll样受体与急性冠脉综合征

免疫炎症反应在急性冠脉综合征的发生、发展中起重要作用。Toll样受体不仅是介导先天免疫和炎症反应的跨膜信号转导受体家族,还是连接天然免疫和获得性免疫的桥梁。越来越多的研究表明Toll样受体4与急性冠脉综合征密切相关。     

Toll样受体在结核分枝杆菌致病机制中的作用研究进展

结核分枝杆菌是肺结核的致病菌,它可寄生在细胞内并长期存活.目前结核杆菌的致病机制及机体对其的免疫反应尚未完全阐明.Toll样受体属于模式识别受体,在结核杆菌宿主防御反应中具有极为重要的作用.Toll样受体作为连接天然免疫与获得性免疫的"桥梁",在机体免疫调节中的作用已愈来愈受关注.关于Toll样受体与结核杆菌的相关研究已成为生命科学领域的热点.     

血管平滑肌细胞TLR4与动脉粥样硬化发展关系的研究进展

目前动脉粥样硬化(AS)被认为是一种慢性炎症过程,Toll样受体4(TLR4)通过激活天然免疫,参与特异性免疫应答的启动,促进炎症的发展,在AS中发挥了重要作用。同时在AS发展过程中血管平滑肌细胞(VSMC)发生增殖、迁移,并分泌细胞因子、趋化因子、蛋白酶等,促进AS的发生、发展。此外,TLR4与VSMC之间存在一定的相互作用,对AS的不同阶段产生影响。     

The role of innate immunity in acute allograft rejection after lung transplantation

Although innate immunity is crucial to pulmonary host defense and can initiate immune and inflammatory responses independent of adaptive immunity, it remains unstudied in the context of transplant rejection. To investigate the role of innate immunity in the development of allograft rejection, we assessed the impact of two functional polymorphisms in the toll-like receptor 4 (TLR4) associated with endotoxin hyporesponsiveness on the development of acute rejection after human lung transplantation. Patients and donors were screened for the TLR4 Asp299Gly and Thr399Ile polymorphisms by polymerase chain reaction using sequence-specific primers. The rate of acute rejection at 6 months was significantly reduced in recipients, but not in donors, with the Asp299Gly or Thr399Ile alleles as compared with wild type (29 vs. 56%, respectively, p = 0.05). This association was confirmed in Cox proportional hazards and multivariate logistic regression models. Our results suggest activation of innate immunity in lung transplant recipients through TLR4 contributes to the development acute rejection after lung transplantation. Therapies directed at inhibition of innate immune responses mediated by TLR4 may represent a novel and effective means to prevent acute rejection after lung transplantation.     

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis

Inflammation and innate immunity may play a role in the pathogenesis of atherosclerosis. The Asp299Gly polymorphism in the toll-like receptor 4 (TLR4) gene reduces responsiveness to lipopolysaccharide and has been associated with reduced incidence and slower progression of carotid atherosclerosis. We analyzed this polymorphism in relation to susceptibility to and severity of coronary artery disease. METHODS: 1400 participants (mean age: 63 years, 31% female) in the Southampton Atherosclerosis Study were genotyped for the TLR4 Asp299Gly polymorphism using the tetra-primer PCR method. RESULTS: There was no significant difference between the frequencies of the Asp/Gly or Gly/Gly genotypes combined, compared to the Asp/Asp genotype, in patients with 0, 1, 2 or 3 coronary arteries with >50% stenosis (chi2(3 d.f.)2=0.4, P=0.94). No associations were observed between genotype groups and cardiac risk factors (P>0.05). CONCLUSION: The findings of this study do not support the hypothesis that the TLR4 Asp299Gly polymorphism influences predisposition to and progression of coronary artery disease.     

CD14 and toll-like receptor 4: a link between infection and acute coronary events?

The CD14 receptor is a pattern recognition molecule in the innate immune response against microorganisms and other exogenous and endogenous stress factors. The most important CD14 signalling co-receptor is toll-like receptor 4 (TLR4), which activates, among others, the nuclear factor kappaB (NF-kappaB) inflammatory pathway. Besides its role in innate immunity and host defence, the proinflammatory cytokines expressed upon TLR4/NF-kappaB pathway activation exert proatherogenic effects. The CD14 C(-260)T promoter and TLR4 Asp299Gly functional polymorphisms have been recently implicated in the development of cardiovascular events, suggesting that the genetically determined inflammatory response against pathogens or their antigens may have a major role in atherogenesis and subsequent acute events. Is the association of these polymorphisms with cardiovascular disease more evidence for the implication of infection, especially by Gram negative bacteria, in the development of acute coronary events? This article reviews the molecular basis, biological functions, and clinical implications of the CD14/TLR4 polymorphisms in the development of cardiovascular events.     

Toll-like receptors: new therapeutic targets for the treatment of atherosclerosis, acute coronary syndromes, and myocardial failure

The toll-like receptors (TLRs) are a class of transmembrane molecules that have important functions in both innate and acquired immunity. As part of the body's normal immune defense against microbial pathogens, stimulation of these receptors will trigger the inflammatory response cascade and the release of cytokines. Activation of these receptors also plays a role in a variety of systemic inflammatory diseases such as asthma, sepsis, atherosclerosis, acute coronary artery disease, and left ventricular remodeling. Pharmacologic approaches to modify the actions of TLRs are now under consideration as potential treatments for inflammatory systemic diseases that include atherosclerosis. At the same time, it is essential to characterize the benefits and risks of modifying such an important part of the body's innate immune system.     

Inhibitory role of toll-like receptors agonists in Plasmodium yoelii liver stage development

It is well known that innate immune plays an important role in controlling the development of Plasmodium liver stage. However, little is known about the role of toll-like receptors (TLR) signalling in the pre-erythrocytic immunity against Plasmodium. Here, we found that pre-treatment with individual TLR agonist pam3CSK4 (TLR2), poly(I:C) (TLR3), LPS (TLR4) and CpG (TLR9) could decrease significantly the liver malaria parasite load in mice for 58%, 63%, 75% and 88% respectively. Moreover, no parasitaemia was observed within 14 days in CpG group mice challenged with 100 sporozoites. At 24 h prior to CpG injection, administration of gadolinium chloride (GdCl₃) led to the rebound of liver Plasmodium load through inhibiting selectively Kupffer cells (KC) phagocytosis capacity but failed to neutralize completely CpG-induced immunity against malaria liver stage. Compared with the control, pre-treatment of CpG up-regulated hepatic pro-inflammatory cytokines IL-12, IFN-γ and TNF-α, but down-regulated anti-inflammatory cytokines IL-10 and TGF-β. Hence, our data demonstrated the inhibitory role of diverse TLR agonists in the Plasmodium development during pre-erythrocytic stage. As the most robust agonist, CpG might inhibit the development of Plasmodium liver stage through regulation of intrahepatic inflammatory cytokines and enhancement of KC cells phagocytosis capacity.     

Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E

Toll-like receptors (TLRs) and the downstream adaptor molecule myeloid differentiation factor 88 (MyD88) play an essential role in the innate immune responses. Here, we demonstrate that genetic deficiency of TLR4 or MyD88 is associated with a significant reduction of aortic plaque areas in atherosclerosis-prone apolipoprotein E-deficient mice, despite persistent hypercholesterolemia, implying an important role for the innate immune system in atherogenesis. Apolipoprotein E-deficient mice that also lacked TLR4 or MyD88 demonstrated reduced aortic atherosclerosis that was associated with reductions in circulating levels of proinflammatory cytokines IL-12 or monocyte chemoattractant protein 1, plaque lipid content, numbers of macrophage, and cyclooxygenase 2 immunoreactivity in their plaques. Endothelial-leukocyte adhesion in response to minimally modified low-density lipoprotein was reduced in aortic endothelial cells derived from MyD88-deficient mice. Taken together, our results suggest an important role for TLR4 and MyD88 signaling in atherosclerosis in a hypercholesterolemic mouse model, providing a pathophysiologic link between innate immunity, inflammation, and atherogenesis.     

Non-high density lipoprotein cholesterol is the best discriminator of myocardial infarction in young individuals

Stroke is one of the leading causes of death in the world. Most stroke patients are classified as having ischemic stroke. The causes of ischemic stroke are very diverse. Atherosclerosis resulting in cerebral or carotid arterial stenosis/occlusion plays the most important role in the occurrence of ischemic stroke. Inflammatory processes or immune responses are involved in the formation of atherosclerosis. Toll-like receptor 4 (TLR4) is a member of the toll-like receptor (TLR) family. TLRs are pattern-recognition receptors, which initiate innate immune responses after interaction with pattern-specific ligands. A polymorphism of the TLR4 gene, Asp299Gly, is associated with an increased risk for coronary heart diseases in Caucasian populations. In this study, we explored the complete coding regions of TLR4 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Single-strand conformation polymorphism (SSCP), and sequencing and found obvious ethnic differences. There was no Asp299Gly polymorphism among the ethnic Chinese examined in this study. We found only one polymorphism on intron 1 (A119C) among our samples. The allele frequencies of 119A were 0.0256 and 0.0022 among the patients and controls, respectively. The odds ratio of 119A of TLR4 in ischemic stroke was 11.71 (95% CI: 1.52–90.01). This polymorphism was significantly associated with ischemic stroke. These data possibly implicate TLR4 as an important genetic factor for stroke in ethnic Chinese populations despite the rarity of the Asp299Gly polymorphism.     

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-beta. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.