Toll-like receptors 3, 7, 8, and 9 in gastric cancer

Toll-like receptors (TLRs) have been shown to have anti-tumor, pro-tumor, or even dual effects in cancer, and are thus potential prognostic biomarkers and immunotherapeutic targets. The present study aimed to evaluate associations between endosomal TLRs, namely TLR3, TLR7, TLR8, and TLR9, expression and clinicopathological variables and survival in gastric cancer. A total of 564 gastric adenocarcinoma patients were included in this retrospective cohort study. Samples and clinicopathological data were retrieved and organized into tissue microarray blocks. Protein expressions were detected by immunohistochemical staining. The patients were divided into low expression and high expression groups by median values of expression. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI), adjusted for confounders. Patients with high nuclear TLR3 expression had significantly poorer 5-year survival than the low nuclear TLR3 expression group in the univariable analysis (crude HR 1.31, 95% CI 1.07–1.60). With radically resected patients, poor prognosis was also seen in the multivariable analysis (adjusted HR 1.38, 95% CI 1.08–1.77). Cytoplasmic TLR3, TLR7, TLR8, and TLR9 were not associated with 5-year survival. In conclusion, high nuclear TLR3 expression seems to have prognostic impact in gastric cancer, while TLR7, TLR8, and TLR9 do not.     

Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity

Summary: Toll-like receptors (TLRs) detect infections by highly conserved components of pathogens that are either not present in our own cells or are normally sequestered in cellular compartments that are inaccessible to the TLRs. Most TLRs are expressed on the cell surface, where they have been shown to detect pathogen-expressed molecules such as lipopolysaccharides and lipopeptides. A subset of TLRs, including TLR3, TLR7, TLR8, and TLR9, are expressed intracellularly within one or more endosomal compartments and detect nucleic acids. Because pathogen and host nucleic acids have very similar structures, these endosomal TLRs may face an extra challenge to induce anti-pathogen immune responses while avoiding the induction of autoimmune diseases. With the rapid growth in understanding of the biology of the TLRs has come an increasing awareness of their effects on autoimmunity, several aspects of which are the focus of this review. First, recent studies have revealed an inappropriate activation of TLR7, TLR8, and TLR9 in systemic lupus erythematosus and several other autoimmune diseases. Secondly, the potential for therapeutic development of TLR antagonists is considered. Finally, with the rapid progress in the development of therapeutic agonists for the TLRs, there is accompanying attention to the theoretical possibility that such therapy may induce autoimmunity or autoimmune diseases.     

A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice

Abstract

Systemic Lupus Erythematosus is an autoimmune disease characterized by production of autoantibodies against nucleic acid-associated antigens. Endogenous DNA and RNA associated with these antigens stimulate inflammatory responses through Toll-like receptors (TLRs) and exacerbate lupus disease pathology. We have evaluated an antagonist of TLR7, 8 and 9 as a therapeutic agent in lupus-prone NZBW/F1 mice. NZBW/F1 mice treated with the antagonist had lower serum levels of autoantibodies targeting DNA, RNP, Smith antigen, SSA and SSB than did untreated mice. Reduction in blood urea nitrogen and proteinuria and improvements in kidney histopathology were observed in antagonist-treated mice. The antagonist treatment also reduced serum IL-12 and IL-1β and increased IL-10 levels. Levels of mRNA for IL-6, iNOS and IL-1β were lower in the kidneys and spleen of antagonist-treated mice than in those of untreated mice. Levels of mRNA for IP-10, TNFRSF9 and FASL were lower and IL-4 mRNA were higher in spleens of antagonist-treated mice than in spleens of untreated mice. mRNA for the inflammasome component NLRP3 was lower and mRNA for the antioxidant enzymes, catalase and glutathione peroxidase 1 was higher in the kidneys of antagonist-treated mice than in those of untreated mice. These results show that the antagonist of TLR7, 8 and 9 effectively inhibits inflammatory pathways involved in the development of lupus in NZBW/F1 mice and constitutes a potential therapeutic approach for the treatment of lupus and other autoimmune diseases.     

Reading the viral signature by Toll-like receptors and other pattern recognition receptors

Successful host defense against viral infections relies on early production of type I interferon (IFN) and subsequent activation of a cellular cytotoxic response. The acute IFN and inflammatory response against virus infections is mediated by cellular pattern-recognition receptors (PRRs) that recognize specific molecular structures on viral particles or products of viral replication. Toll-like receptors (TLRs) constitute a class of membrane-bound PRRs capable of detecting microbial infections. While TLR2 and TLR4, which were first identified to recognize Gram-positive and Gram-negative bacteria, respectively, sense specific viral proteins on the cell surface, TLRs 3, 7, 8, and 9 serve as receptors for viral nucleic acids in endosomic compartments. In addition to TLRs, cells express cytoplasmic PRRs such as the RNA helicase retinoic acid inducible gene I and the kinase double-stranded RNA-activated protein kinase R, both of which sense dsRNA, a characteristic signature of viral replication, and initiate a protective cellular response. Here we review the recent progress in our understanding of PRRs and viral infections and discuss the molecular and cellular responses evoked by virus-activated PRRs. Finally, we look into what is currently known about the role of PRRs in viral infections in vivo.     

TLRs与同种异型移植排斥

Toll样受体(Toll-like receptors,TLRs)是一类在机体识别、清除入侵病原微生物免疫过程中起重要作用的受体.除此之外,新近的研究表明TLRs还参与同种异型移植过程中的排斥反应.本文就TLRs的这一进展进行了综述,内容包括TLRs的结构、功能和信号通路,TLRs与无菌性炎症,以及TLRs与皮肤、内脏移植排斥.     

Toll样受体与抗真菌免疫

Toll样受体（TLR）是固有免疫系统中特异的I型跨膜蛋白,能广泛识别细菌、真菌及病毒等表面保守的病原相关分子模式（PAMP）,传导炎症信号,介导多种生物学效应,是联系固有免疫和适应性免疫的桥梁。已证实TLR能够通过识别真菌表面某些PAMP,激活巨噬细胞和中性粒细胞的吞噬作用并释放各种炎性细胞因子,从而起到抗真菌作用。对TLR进一步深入研究将有可能为真菌感染性疾病的免疫治疗提供新的思路。     

Toll样受体介导抗HBV感染免疫

Toll样受体(TLRs)的发现,使人们对HBV感染免疫有了新的认识.目前研究认为,TLRs除了介导抗HBV感染天然免疫外,还能促进树突状细胞(DC)成熟,调节Th1/Th2型免疫,参与抗HBV特异性免疫,同时,HBV也影响某些TLRs的表达,这可能是HBV感染慢性化的原因之一.进一步明确TLRs在HBV感染免疫中的作用,可为HBV感染的治疗提供一个新的切入点.     

Toll-like receptors in the skin

Toll-like receptors (TLRs) are important pattern-recognition receptors involved in host defense against a variety of pathogenic microorganisms. Activation of TLRs leads to the production of cytokines, chemokines, antimicrobial peptides, and upregulation costimulatory and adhesion molecules involved in innate and adaptive immune responses. TLRs are expressed on a variety of cell types found in the skin, including keratinocytes and Langerhans cells in the epidermis, resident and trafficking immune-system cells such as macrophages, dendritic cells, T and B cells, and mast cells in the dermis, endothelial cells of the skin microvasculature, and skin stromal cells such as fibroblasts and adipocytes. There have been an increasing number of reports demonstrating that TLRs play a key role in cutaneous host defense mechanisms against bacterial, fungal, and viral pathogens. In addition, TLRs have also been implicated in the pathophysiology of various inflammatory skin diseases.     

Toll-like receptor 8 deletion accelerates autoimmunity in a mouse model of lupus through a Toll-like receptor 7-dependent mechanism

Systemic lupus erythematosus is an autoimmune disorder characterized by increased levels of lymphocyte activation, antigen presentation by dendritic cells, and the formation of autoantibodies. This leads to immune complex-mediated glomerulonephritis. Toll-like receptor 7 (T7) and TLR9 localize to the endosomal compartment and play important roles in the generation of autoantibodies against nuclear components, as they recognize RNA and DNA, respectively. In contrast, very little is known about endogenous TLR8 activation in mice. We therefore tested whether TLR8 could affect autoimmune responses in a murine model of lupus. We introduced a Tlr8 null mutation into C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus and bearing the Yaa (Y-linked autoimmune acceleration) mutation containing a tlr8 duplicated gene, and monitored disease development, autoantibody production, and glomerulonephritis-associated mortality. Cellular responses were investigated in female Nba2.TLR8^−/− mice bearing no copy of tlr8. The TLR8 deficiency accelerated disease progression and mortality, increased the number of circulating antibodies and activated monocytes, and heightened cellular responses to TLR7 ligation. TLR8-deficient antigen-presenting cells exhibited increased levels of MHC class II expression. The ability of dendritic cells to present antigens to allogeneic T cells after TLR7 ligation was also improved by TLR8 deficiency. TLR8 deletion accelerated autoimmunity in lupus-prone mice in response to TLR7 activation. Antigen-presenting cell function seemed to play a key role in mediating the effects of TLR8 deficiency.     

Therapeutic targeting of Toll-like receptors: a review of Toll-like receptors and their signaling pathways in psoriasis

Introduction: Expression of various Toll-like receptors (TLR) in keratinocytes (KCs) has offered new insights into the pathogenesis of psoriasis. When plasmacytoid dendritic cells (pDCs) are scarce in established psoriatic lesions, KCs take the responsibility to secrete IFN type 1 through TLR9 activation. Antagonists of TLR7 and TLR8 and anti-IL-12/IL-23 substances have shown promising results in treating psoriasis.

Areas covered: References in this study were extracted from Scopus, PubMed and Embase databases by the search term: (‘Toll-Like Receptors’ OR ‘TLR’) AND (‘Psoriasis’ OR ‘Arthritis, Psoriatic’ OR ‘PsA’).

Expert commentary: As the prevailing cell type, KCs play a major role in the maintenance of psoriatic lesions. By specific upregulation of IL-36 R, KCs can start the IL-23/IL-12 axis, leading to production of major culprits of psoriatic phenotype IL-17 and IL-22. Targeting IL-36 R could be considered as a new therapeutic target to eliminate cutaneous manifestations of psoriasis.     

Toll-like receptors and atherosclerosis

The identification of Toll-like receptors (TLRs) as key patten-recognition receptors of innate immunity has opened inquiries into previously unknown disease mechanisms. The ability of TLRs to detect a spectrum of pathogen-derived molecules defines their importance in innate immunity and provides a mechanistic link between infection and disease. Atherosclerosis is a chronic inflammatory disease where immune and metabolic factors interact to initiate and propagate arterial lesions. An understanding of TLRs in atherosclerosis could clarify the etiology of this complex process. Furthermore, the existence of host-derived endogenous TLR ligands may implicate TLR involvement in disease mechanisms beyond innate immunity, such as a role in homeostatic mechanisms to resolve injury. Our current knowledge of TLRs in atherosclerosis is discussed in this review with emphasis on experimental studies in atherosclerosis-susceptible mouse models. Highlights from studies of TLR involvement in other disease processes have demonstrated that TLR-dependent mechanisms probably parallel those found in atherosclerosis, some of which could be important in mitigating atherosclerotic injury. Finally, an appreciation of the pro- and anti-atherosclerotic mechanisms of TLR activation over the entire lifetime of an organism will provide clues to the role of TLRs in both health and disease.     

Menstrual cycle-dependent changes of Toll-like receptors in endometrium

BACKGROUND: Rapid innate immune defences against infection usually involve the recognition of invading pathogens by specific pattern recognition receptors recently attributed to the family of Toll-like receptors (TLRs). Reports from our laboratory and others have demonstrated the existence of TLRs 1-6 in the female reproductive tract. However, little has been done to identify TLRs 7-10 in the female reproductive tract, particularly in the uterus. Also little information exists regarding variation in TLRs in the female reproductive tract during the menstrual cycle. METHOD: The distribution of TLR7-10 protein was detected by immunostaining in timed endometrial biopsies from normal women. RT-PCR was used to show the existence of TLR1-10 genes in endometrial tissue and real-time PCR analysis to investigate the relative expression of these genes during the menstrual cycle in normal human endometrium. RESULTS: TLR7-10 proteins were detected in endometrial epithelium and stroma. TLR1-10 genes were expressed in human endometrial tissue, and the mean relative expression of TLR2-6, 9 and 10 genes was significantly higher during the secretory phase compared with other phases of the menstrual cycle. CONCLUSIONS: TLR7-10 localization is not limited to endometrial epithelium but is also present in the stroma of the endometrial tissue. Endometrial TLR2-6, 9 and 10 genes are cyclically expressed during the menstrual cycle.     

Impaired expression of indoleamine 2, 3-dioxygenase in monocyte-derived dendritic cells in response to Toll-like receptor-7/8 ligands

The endogenous cannabinoid system plays an important role in regulating the immune system. Modulation of endogenous cannabinoids represents an attractive alternative for the treatment of inflammatory disorders. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme catalysing degradation of the endogenous cannabinoid anandamide, and AM404, an inhibitor of anandamide transport, on lipopolysaccharide (LPS)-induced increases in plasma cytokine levels in rats. Both URB597 and AM404 potentiated the LPS-induced increase in plasma tumour necrosis factor-alpha (TNF-alpha) levels. The peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW9662, attenuated the AM404-induced augmentation of TNF-alpha levels. Furthermore, the selective cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630 respectively, and the transient receptor potential vanilloid receptor-1 (TRPV1) antagonist, SB366791, reduced LPS-induced TNF-alpha plasma levels both alone and in combination with AM404. In contrast, AM404 inhibited LPS-induced increases in circulating interleukin-1beta (IL-1beta) and IL-6. AM251 attenuated the immunosuppressive effect of AM404 on IL-1beta. None of the antagonists altered the effect of AM404 on LPS-induced IL-6. Moreover, AM251, AM630 and SB366791, administered alone, inhibited LPS-induced increases in plasma IL-1beta and IL-6 levels. In conclusion, inhibition of endocannabinoid degradation or transport in vivo potentiates LPS-induced increases in circulating TNF-alpha levels, an effect which may be mediated by PPARgamma and is also reduced by pharmacological blockade of CB1, CB2 and TRPV1. The immunosuppressive effect of AM404 on IL-1beta levels is mediated by the cannabinoid CB1 receptor. Improved understanding of endocannabinoid-mediated regulation of immune function has fundamental physiological and potential therapeutic significance.     

Severe sepsis and Toll-like receptors

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.     

Toll样受体在结核病免疫应答中的作用

结核病(Tuberculosis)主要是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)引起的重大传染性疾病。Toll样受体(Toll-like receptors,TLRs)在宿主的抗结核免疫应答中发挥重要作用。研究表明,TLR1、2、4、6和9与宿主抗MTB感染有关,其中TLR2的作用更为突出。免疫应答的早期阶段,TLR2介导了巨噬细胞的活化,通过产生具有直接杀伤效应的分子或者诱导宿主细胞的凋亡抑制MTB的增殖。然而TLR2介导的信号通路也可通过降低MHC-Ⅱ分子的表达来削弱抗原递呈的能力,促进MTB在宿主内的存活。近几年临床研究发现TLRs多态性位点与结核病易感有关也从侧面证实了TLRs在抗MTB感染中发挥重要作用。     

栀子苷下调Toll样受体4表达并拮抗脂多糖诱导的小胶质细胞炎性反应

目的:观察栀子昔对细菌脂多糖(LPS)诱导的BV2小胶质细胞炎性反应的影响并探讨其作用机制。方法:LPS诱导BV2小胶质细胞活化,CCK-8方法检测细胞存活率,Griess法测定NO释放量,ELISA测定肿瘤坏死因子-α(TNF-α)和白介素-1β(IL-1β)含量,免疫印迹检测Toll样受体4(TLR4)蛋白表达。结果:栀子苷在10～100μg/ml浓度范围内对小胶质细胞活力影响不显著,此浓度范围内,栀子苷剂量依赖性的减少LPS诱导的NO、TNF-α和IL-1β释放。此外,栀子苷还可抑制LPS诱导的BV2细胞形态活化改变,并降低LPS诱导的TLR4蛋白表达。结论:栀子苷可以拮抗LPS诱导的BV2小胶质细胞炎性反应,其机制可能与下调TLR4信号通路有关。     

The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity

Dendritic cells which are located at the interface of innate and adaptive immunity are targets for infection by many different DNA and RNA viruses. Dendritic cell subpopulations express specific nucleic acid recognition receptors belonging to the Toll-like receptor family (TLR3, 7, 8, 9) and the cytosolic RNA helicase family (RIG-I, MDA5, LGP2). Activation of dendritic cells by viral DNA and RNA via these receptors is essential for triggering the innate antiviral immune response and shaping the ensuing adaptive antiviral immunity. This review will summarize our current knowledge of viral nucleic acid recognition and signaling by Toll-like receptors and RNA helicases focusing on recent evidence for their specific functions in antiviral defense in vivo.     

Characterization of Toll-like receptors in the female reproductive tract in humans

BACKGROUND: Rapid innate immune defences against infection involve the recognition of invading pathogens by specific pattern recognition receptors recently attributed to the family of Toll-like receptors (TLR). Little is known about the in vivo protein expression or distribution of TLR in the female reproductive tract in humans. It is likely that TLR distribution in the female reproductive tract reflects the immunological tolerance to the commensal organisms in lower parts of the tract (vagina, ectocervix and, partially, endocervix) and the intolerance to commensal microbial flora in the upper tract (the uterus and uterine tubes). METHODS: Using immunohistochemistry techniques, distribution of TLR1-6 was studied in surgical sections from the vagina, ecto- and endocervix, endometrium and uterine tubes, obtained from patients undergoing abdominal hysterectomy for benign gynaecological conditions. RESULTS: TLR1, 2, 3, 5 and 6 were present in the epithelia of different regions of female reproductive tract. However, TLR4 was only present in the endocervix, endometrium and uterine tubes and absent in vagina and ectocervix. In addition, a secretory form of TLR4 seems to be produced by the endocervical glands. CONCLUSION: TLR4 may play an important role in modulation of immunological tolerance in the lower parts of the female reproductive tract, and in host defence against ascending infection.     

Toll-like receptors in Borrelia burgdorferi-induced inflammation

Lyme arthritis, the most common manifestation of late Lyme disease, has been associated with the presence of Borellia burgdorferi in the joint. However, it is still unclear whether the pathogen itself is able to elicit such a sustained inflammatory response, or whether an aberrant immunological reaction of the host is the main driving force. Borrelia antigens, including lipoproteins, flagellin and DNA, are ligands of Toll-like receptors, and can thus elicit a strong stimulation of host cells, such as neutrophils, mononuclear cells and resident tissue cells. Understanding the molecular basis of the signalling events caused by Borrelia lipoproteins will lead to a greater understanding of inflammation in Lyme arthritis and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.