Toll样受体通路调节Tregs功能的研究进展

模式识别受体Toll样受体(Toll like receptors,TLRs)是固有免疫中免疫受体的代表,进化上十分保守,对生物体的生存极为重要。TLRs通过内源或外源的配体启动信号转导,激活下游一系列重要的基因表达与活化。研究表明调节性T细胞(Regulatory T cell,Treg)在维持机体外周免疫耐受和阻止移植排斥反应等方面发挥核心作用。Treg细胞表达某些TLRs,包括TLR2、TLR4、TLR5、TLR7、TLR8、TLR9等。TLRs的活化可能直接或间接地影响(主要是活化) Treg的增殖和免疫抑制功能,这种调节与感染、自身免疫病和癌症的发生密切相关。其中热休克蛋白作为TLRs配体分子对于Treg的调节发挥了重要的作用。因此,了解TLRs通路对研究Treg免疫调控机制、新药物研发和靶向治疗有重大意义。文中简要介绍了TLRs通路调节Treg免疫功能的相关研究进展。     

树突状细胞与Toll受体研究新进展

树突状细胞是最强的抗原提呈细胞,在免疫系统中发挥着重要作用。Toll样受体是表达在树突状细胞上的一种PRRs,主要功能是通过识别病原体微生物所携带的病原相关分子模式激活DC,使其分泌各种免疫调节细胞因子,从而启动免疫应答。在肠道免疫中TLR信号的激活为肠道提供保护作用。本文简述了树突状细胞的生物特性、不同亚型。重点阐述了Toll样受体在肠道免疫中的作用及益生菌对肠道Toll样受体表达的影响。     

Toll样受体4对动脉粥样硬化发生、发展的研究进展

动脉粥样硬化（atherosclerosis,AS）是多种细胞、炎性介质参与形成的慢性炎症性疾病。Toll样受体家族（Toll like receptors,TLRs）中的TLR4是机体重要的诱导分泌多种炎性因子的模式识别受体。现有证据表明,TLR4不仅产生多种炎性因子诱发血管炎症反应,而且促进AS斑块形成和发展,造成斑块不稳定,甚至破裂,对AS的发生、发展具有重要作用。因此,了解TLR4对AS的影响有助于发现新的治疗靶点和对策。主要对TLR4在AS发病机制和易损斑块发展中的作用进行综述。     

Toll样受体识别机制及其生物学意义

Toll样受体介导的信号转导通路在对抗外来病原体的天然免疫应答中起重要作用。Toll样受体是一个天然模板识别受体家族,能识别固有性模板(微生物和哺乳动物所共有的病原相联的分子模板PAMPs)。Toll样受体通过巨噬细胞和其他免疫细胞来识别,其中TLR4识别内毒素、TLR2识别肽聚糖、TLR9识别细菌DNA、TLR5识别鞭毛蛋白、TLR3识别双链RNA等。本探讨了多种Toll受体家族成员在动物体内识别机理及功能,概述了其应用研究进展。     

固有免疫应答与动脉粥样硬化关系的研究进展

固有免疫应答在动脉粥样硬化(atherosclerosis,As)的发生和发展中起重要作用．固有免疫应答细胞,包括单核/巨噬细胞、肥大细胞、自然杀伤细胞、中性粒细胞和树突状细胞,是机体抵御微生物和异物入侵的第一道防线．这些细胞广泛参与As中泡沫细胞形成、斑块内基质降解、细胞凋亡、血管新生和斑块破裂等事件．模式识别受体是免疫细胞上识别病原体(或某些内源性成分)相关分子模式的一类受体分子,包括Toll样受体和NOD样受体,介导固有免疫应答反应．Toll样受体在固有免疫应答细胞中具有不同程度的表达,在As中具有不同的作用,如TLR2和TLR4对As起促进作用,而TLR3具有As保护作用．NLRP3炎性体与动脉血管壁的早期损伤有关．对固有免疫应答细胞及模式识别受体在As形成中的作用进行深入研究,不仅有助于理解As的形成过程,而且还能为临床上防治心血管类疾病提供了新的治疗靶点和诊断指标．     

Toll样受体与肿瘤免疫

Toll样受体(Toll-like receptor)是天然免疫系统中最重要的模式识别受体,在病原体感染过程中对入侵病原体的识别,激活免疫应答起重要作用。近年发现Toll样受体在多种肿瘤的发生过程中起重要的调控作用。Toll样受体在肿瘤细胞中具有表达,并且Toll样受体信号诱导的促炎症反应是肿瘤发生的必要条件,但是有些Toll样受体的配体仍然表现出极强的抗肿瘤活性,目前,Toll样受体在肿瘤免疫中的机制研究已经成为Toll样受体作为药物靶点的临床应用的关键。本文对Toll样受体在肿瘤免疫中的机制进行综述。     

TLR9的生物学特性及其在心血管疾病中的研究进展

Toll样受体(toll-like receptors,TLRs)是一类保守的介导固有免疫的跨膜信号传递受体家族,是一种I型跨膜蛋白受体,是模式识别受体(pattern recognition receptor,PRR)中的一员,在识别和抵御各种病原微生物及其产物的过程中发挥重要作用。病原微生物呈现多种真核细胞不具备的特殊的保守结构,称为病原相关分子模式(pathogen associated molecular patterns,PAMPs),这种结构可被PRR所识别,并通过下游的接头蛋白引发转录因子的激活和炎症因子的产生。不同的TLR分子具有各自特异的PAMPs识别谱,其中Toll样受体9(TLR9)是识别细菌来源的非甲基化CpG DNA等PAMPs的受体。TLRs在固有免疫和适应性免疫中发挥着重要作用,并参与多种心血管疾病的发病过程。本文就TLR9的生物学特性及其在心血管疾病中的研究进展进行综述。     

TLR/MyD88信号通路与自身免疫性疾病

Toll样受体(Toll-like receptor,TLR)是近年来发现的一类模式识别受体,通过识别病原相关分子模式(pathogen-associated molecular pattern,PAMP),激活天然免疫.TLR信号还通过上调抗原提呈细胞(antigen presenting cells,APC)表面共刺激分子及APC分泌的炎症细胞因子调节获得性免疫.TLR/MyD88信号在自身免疫性疾病的发病过程中起重要作用.本文介绍了TLR/MYD88信号通路及其在自身免疫病如实验性自身免疫脑脊髓膜炎、类风湿性关节炎、实验性自身免疫性葡萄膜炎、实验性自身免疫性心肌炎和自身免疫性肾小球肾炎等发生发展中的作用.     

Toll样受体4表达的调节

Toll样受体4(TLR4)是最早发现的人类Toll样受体,主要表达于树突状细胞和巨噬细胞等免疫细胞表面,在免疫应答和炎症反应中起重要作用。本文综述了影响TLR4表达的包括上调因素和下调因素在内的一些主要调节因素。     

Toll样受体4与肝损伤的研究进展

Toll样受体4((toll like receptor4,TLR4)是内毒素(LPS)的关键受体,为Toll蛋白家族中的一个成员,是联系固有免疫和适应性免疫的纽带。TLR4主要表达于髓源性细胞,其启动的胞内信号转导在肝损伤的发生和发展过程中发挥重要作用。这一信号转导途径主要通过NF-κB、p38、JNK等的激活,使细胞产生炎症转录因子,介导肝脏炎症。TLR4与氧化应激的相互作用,使得肝脏对TLR4的配体及细胞因子的敏感性增加,从而加重肝脏损伤。随着TLR4在肝损伤中的作用进一步阐明,其在肝脏疾病中的治疗作用将会产生广阔的应用前景。     

Functional role for toll-like receptors in atherosclerosis and arterial remodeling

PURPOSE OF REVIEW: Activation of inflammatory cascades is causally related to the development of atherosclerotic disease. Toll-like receptors are innate immune receptors that recognize pathogen-associated molecular patterns. In this review the pathways by which toll-like receptors might play a role in the development and progression of atherosclerosis will be discussed according to recent literature. RECENT FINDINGS: Toll-like receptors are expressed in atherosclerotic tissue. Next to pathogens, endogenous toll-like receptor ligands have been linked with the development of arterial occlusive disease. In mouse models of hyperlipidemia, a potential role for the toll-like receptor pathway has been suggested in hypercholesterolemia-induced atherosclerosis. Recent in-vitro studies revealed a mechanism by which toll-like receptor ligation results in a strong inhibition of cholesterol efflux from macrophages. In addition, oxidized lipoproteins interact with toll-like receptors. Furthermore, activation of the apoptotic cascade, which is important during atherogenesis, enhances the toll-like receptor pathway resulting in upregulation of proinflammatory cytokines. Human epidemiologic studies have linked TLR4 polymorphism with atherosclerosis. However, data on the association between atherosclerosis progression and TLR4 polymorphisms are conflicting. Next to plaque growth, arterial remodeling is an important determinant of luminal narrowing in atherosclerosis. Recently, a possible role for TLR4 signaling in arterial remodeling has been revealed in mouse models. SUMMARY: A clarification of the molecule [corrected] mechanisms by which the toll-like receptor signaling cascade influences atherosclerosis might [corrected] lead to novel strategies to intervene in the development of this life-threatening disease.     

TLR9与先天性免疫反应

TLR9（Toll-likereceptor9）是一种微生物病原相关分子结构模式识别受体,TLR9能够识别CpG—ODN（胞嘧啶磷酸鸟甘-寡聚脱氧核苷酸）,使病原相关受体在先天性免疫细胞上表达,并激活下游炎性通路。研究表明,TLR9在先天性免疫反应中产生了重要作用,如脓毒血症、自身免疫性疾病、刀豆体球蛋白A介导肝炎性肝脏损伤、炎性泡沫细胞形成、缺血再灌注损伤等,并且与多种致病因子相关联,如肝x受体、甲酰多肽受体、线粒体DNA等。     

Multiple roles of Toll-like receptor signaling in atherosclerosis

PURPOSE OF REVIEW: Toll-like receptors are key regulators of both innate and adaptive immune responses. This review outlines the recently emerged multiple roles of Toll-like receptor signaling in atherosclerosis. RECENT FINDINGS: Mice deficient in TLR4, TLR2 and MyD88 all have reduced atherosclerosis which establishes that Toll-like receptor-dependent pathways contribute to disease development. Although it is likely that total "infectious burden" contributes to atherosclerosis progression, endogenous ligands may also initiate and modulate Toll-like receptor signaling pathways. CD36, with established roles in recognition of endogenous ligands and atherosclerotic disease, facilitates TLR2 signaling and might therefore represent a bridge between endogenous lipid ligands and Toll-like receptor pathways. Furthermore, lipoprotein oxidation generates ligands that activate Toll-like receptor pathways. At the same time, Toll-like receptor activation may be inhibited by accumulating oxidized phospholipids, which could result in reduced dendritic cell maturation and impaired immunological priming. SUMMARY: Activation of Toll-like receptor signaling can promote atherosclerosis by multiple mechanisms, while some beneficial Toll-like receptor pathways may be inhibited by lipid accumulation. Due to their central role in the disease process, Toll-like receptor signaling pathways represent a target of immunomodulatory therapy with the goal of tipping the balance from excessive chronic inflammation towards resolution of inflammation, while not compromising host defense or atheroprotective immune functions.     

The role of DNA sensing and innate immune receptor TLR9 in otitis media

Otitis media (OM), a common infectious disease in children, is associated with bacterial middle ear (ME) infection. Toll-like receptors (TLRs) are important mediators of innate immune responses, and TLR9 specifically recognizes the unmethylated cytidine-phosphate-guanosine (CpG) motifs in bacterial DNA. Additional sensors of foreign DNA have recently been identified. The role of DNA sensing and TLR9 was investigated in a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). Expression of genes related to DNA-sensing pathways involved in innate immunity was assessed via DNA microarray, qPCR and immunohistochemistry. Middle ear responses to NTHi were examined in wild-type and TLR9(-/-) mice by histopathology and bacterial culture. Expression of TLR9 signaling genes was modestly up-regulated during OM, as was TLR9 protein in both ME mucosal cells and infiltrating leukocytes. However, genes known to be regulated by CpG DNA were dramatically up-regulated, as were genes involved in DNA sensing by DIA, Pol-III and AIM2. Toll-like receptor 9 deletion significantly prolonged the inflammatory response induced by NTHi in the ME and delayed bacterial clearance. The results suggest that DNA sensing via TLR9 plays a role in OM pathogenesis and recovery. Alternative forms of DNA sensing may also contribute to OM.     

Toll-like receptors in the functional orientation of cardiac progenitor cells

Cardiac progenitor cells (CPCs) have the potential to differentiate into several cell lineages with the ability to restore in cardiac tissue. Multipotency and self-renewal activity are the crucial characteristics of CPCs. Also, CPCs have promising therapeutic roles in cardiac diseases such as valvular disease, thrombosis, atherosclerosis, congestive heart failure, and cardiac remodeling. Toll-like receptors (TLRs), as the main part of the innate immunity, have a key role in the development and differentiation of immune cells. Some reports are found regarding the effect of TLRs in the maturation of stem cells. This article tried to find the potential role of TLRs in the dynamics of CPCs. By showing possible crosstalk between the TLR signaling pathways and CPCs dynamics, we could achieve a better conception related to TLRs in the regeneration of cardiac tissue.     

Lack of an antibacterial response defect in Drosophila Toll-9 mutant

Toll and Toll-like receptors represent families of receptors involved in mediating innate immunity response in insects and mammals. Although Drosophila proteome contains multiple Toll paralogs, Toll-1 is, so far, the only receptor to which an immune role has been attributed. In contrast, every single mammalian TLR is a key membrane receptor upstream of the vertebrate immune signaling cascades. The prevailing view is that TLR-mediated immunity is ancient. Structural analysis reveals that Drosophila Toll-9 is the most closely related to vertebrate TLRs and utilizes similar signaling components as Toll-1. This suggests that Toll-9 could be an ancestor of TLR-like receptors and could have immune function. Consistently, it has been reported that over-expression of Toll-9 in immune tissues is sufficient to induce the expression of some antimicrobial peptides in flies. These results have led to the idea that Toll-9 could be a constitutively active receptor that maintain significant levels of antimicrobial molecules and therefore provide constant basal protection against micro-organisms. To test theses hypotheses, we generated and analyzed phenotypes associated with a complete loss-of-function allele of Toll-9. Our results suggest that Toll-9 is neither required to maintain a basal anti-microbial response nor to mount an efficient immune response to bacterial infection.     

Innate immunity: structure and function of TLRs

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate na?ve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.     

The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Toll-like receptors (TLRs) recognize Brucella spp. and bacterial components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella infection. TLR2, TLR4 and TLR9 have been implicated in host interactions with Brucella; however, TLR9 has the most prominent role. Further, the relationship between specific Brucella molecules and various signal transduction pathways needs to be better understood. MyD88-dependent and TRIF-independent signaling pathways are involved in Brucella activation of innate immune cells through TLRs. We have recently reported the critical role of MyD88 molecule in dendritic cell maturation and interleukin-12 production during B. abortus infection. This article discusses recent studies on TLR signaling and also highlights the contribution of NOD and type I IFN receptors during Brucella infection. The better understanding of the role by such innate immune receptors in bacterial infection is critical in host-pathogen interactions.     

Lung cancer and Toll-like receptors

Lung carcinoma is one of the leading causes of death worldwide. It is a non-immunogenic cancer, resistant to immune surveillance. Toll-like receptors (TLRs) connect the innate to the adaptive immune system. Given that cancerous cells evade the immune system, the activation of TLRs could represent a potential target for cancer therapy. The induction of Th1-like and cytotoxic immunity by TLR signalling could lead to tumour cell death, resulting in tumour regression or arrest. However, basic research and clinical trials revealed that the activation of specific TLRs, such as TLR2, TLR4 and TLR9, do not have any anti-tumour activity in lung carcinoma. Increasing evidence suggests that TLRs are important regulators of tumour biology; however, little is known about their function in lung cancer. Thus, in order to develop new therapeutic approaches, further studies are needed to understand the connection between TLRs and lung cancer progression. This review focuses on the potential mechanisms by which TLR ligands can facilitate or not lung cancer and lung metastases establishment/progression.