The IUPHAR/BPS Guide to Pharmacology. TLR2 - Toll-like receptor family. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.

By virtue of its direct contact with the environment, the lung is constantly challenged by infectious and non-infectious stimuli that necessitate a robust yet highly controlled host response coordinated by the innate and adaptive arms of the immune system. Mammalian Toll-like receptors (TLRs) function as crucial sentinels of microbial and non-infectious antigens throughout the respiratory tract and mediate host innate immunity. Selective induction of inflammatory responses to harmful environmental exposures and tolerance to innocuous antigens are required to maintain tissue homeostasis and integrity. Conversely, dysregulated innate immune responses manifest as sustained and self-perpetuating tissue damage rather than controlled tissue repair. In this article we review aspects of Toll-like receptor function that are relevant to the development of acute lung injury and chronic obstructive lung diseases as well as resistance to frequently associated microbial infections.

Activation of TLRs contributes to both infectious and non-infectious CNS diseases [13]. So far, common approaches to unravel the influence of TLRs in the CNS used mice deficient of one TLR or of their signaling adaptors or made use of a single ligand that is highly specific for activation of the respective TLR. However, although the pathophysiological relevance of the different TLR ligands for the brain has not yet been conclusively clarified, it can be reasonably assumed that more than one TLR is involved in physiological and pathological processes within the CNS, and molecules that activate TLRs are likely be present as a mixture at one time. We sought to analyze the impact of single and pairwise TLR activation on inflammation and neurodegeneration in the CNS.. Studies on models of systemic infectious diseases indicate that TLR family members act in concert to induce an effective antibacterial response [32],[33]. This concept of receptor redundancy certainly makes sense, especially in the CNS, ...

Atherosclerosis is the underlying cause of coronary artery disease and cerebrovascular disease. Risk prediction of cardiovascular disease and subsequent clinical manifestations are mainly based on models including hypercholesterolemia and smoking, but these models do not always work on an individual level. Therefore, there is an urgent need for biomarkers. Atherosclerosis ... read more is considered an inflammatory disease in which innate immune cells like monocytes and neutrophils play a prominent role. Toll-like receptors (TLRs), which are abundantly expressed by these cells, are important receptors for the activation of the immune system. These receptors respond to exogenous ligands derived from pathogens, but also to endogenous triggers. Ligand binding to TLRs results in the transcription of pro-inflammatory and pro-atherogenic mediators like cytokines and increased expression of cell adhesion molecules, but it has also been reported that repetitive TLR stimulation results in attenuated TLR ...

Mast cells are sentinel cells that are found distributed within the connective tissue throughout the body and play an important role in both acute and chronic inflammation. Mast cells that are coated with IgE antibodies specific for certain environmental antigens are triggered to release histamine and other cytokines that induce early vascular changes that are hallmarks of acute inflammation. [51] The immediate responsibility of mast cells is to recognise that infection by a pathogen has occurred, which is achieved by direct recognition of the pathogen by pattern recognition receptors that are activated in response to pathogen-associated molecular patterns (PAMPs). [52] A study conducted by Supajatura et al. demonstrated that the activation of different toll-like receptors (TLR2 or TLR4) by varying PAMPs resulted in differential activation of mast cells evident in lypopolysaccharide stimulation of TLR4 resulting in cytokine release compared to peptidoglycan stimulation of TLR2 receptors ...

Recognition of pathogens by the innate immune system activates Toll-like receptor (TLR)-mediated pathways, resulting in NF-κB-induced transcription of inflammatory cytokines (1). These molecules subsequently direct the initiation of appropriate adaptive responses, leading ultimately to clearance or containment of the invading pathogen (2). Due to their potent biological activity, however, inappropriately prolonged or excessive release of proinflammatory mediators can result in deleterious effects for the host. This is exemplified by the acute-phase cytokine IL-6, whose role in the development of the potentially pathogenic Th17 subset of T cells has recently been described (3). Furthermore, therapies targeting the cytokines IL-1, IL-6, and TNF-α have all shown promising efficacy in the treatment of autoimmune disorders, implying a central role for these molecules in disease pathogenesis (4, 5).. Given the dual nature of proinflammatory cytokines-essential for host defense but potentially lethal ...

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by Daffolyn Rachael Fels Elliott, Juliane Perner, Xiaodun Li, Martyn F. Symmons, Brett Verstak, Matthew Eldridge, Lawrence Bower, Maria ODonovan, Nick J. Gay, the OCCAMS Consortium , Rebecca C. Fitzgerald Esophageal adenocarcinoma (EAC) develops in an inflammatory microenvironment with reduced microbial diversity, but mechanisms for these influences remain poorly characterized. We hypothesized that mutations targeting…

Mammalian TLRs play a central role in innate immunity by mediating recognition of pathogen-associated microbial patterns. Human polymorphisms in TLR2 and TLR4 are associated, respectively, with increased susceptibility to S. aureus infections (9) and LPS hyporesponsiveness (12) underscoring the importance of intact PAMP recognition systems in human health. In addition to immune functions, invertebrate TLRs have been shown to act during development and in cell to cell interactions (31, 32, 33). Further complexity in understanding TLR biology arises from the recognition that some TLRs act as coreceptors (e.g., TLR1, TLR6) with other TLRs (e.g., TLR2) and can promote or inhibit cellular responsiveness to activating ligands (26, 34). To identify settings both within the immune system and throughout the body in which TLRs may regulate important biological processes, we initiated a study of the expression of human TLRs.. Consistent with their roles in immune surveillance, TLR mRNAs are expressed at ...

This Bovine Toll-like receptor 3 (TLR3) ELISA Kit employs a two-site sandwich ELISA to quantitate TLR3.,TLR3; CD283;,TLR 3 is a member of the Toll-like receptor family of pattern recognition receptors of the innate immune system. Discovered in 2001,TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as reoviruses. Upon recognition, TLR 3 induces the activation of NF-kB to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5.The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute. TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a

TY - JOUR. T1 - Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells. AU - Lech, M.. AU - Garlanda, C.. AU - Mantovani, A.. AU - Kirschning, C. J.. AU - Schlöndorff, D.. AU - Anders, H. J.. PY - 2007/7. Y1 - 2007/7. N2 - Toll-like receptors (TLRs) exist on both myeloid and intrinsic renal cells contributing to the initiation of innate immunity during renal infection with uropathogenic Escherichia coli. Toll-interleukin 1 receptor (IL-1R) (TIR)8/SIGIRR is an orphan receptor of the TLR/IL-1R family, which suppresses TLR signaling of immune cells and is highly expressed in the kidney. Lack of TIR8/SIGIRR is associated with enhanced renal chemokine signaling upon exposure to lipopolysaccharide (LPS). This was because of TIR8/SIGIRR expression on resident intrarenal myeloid cells rather than tubular epithelial cells which express it on basolateral and luminal membranes. The lack of TIR8/SIGIRR does not enhance TLR/IL-1R ...

Toll-like receptors are pattern-recognition receptors that have key roles in detecting microbes and initiating inflammatory responses. Recently, a host of new microbial products that activate specific Toll-like receptors have been defined, and additional components that mediate intracellular signali …

Oh, Djin-Ye; Baumann, Konstantin; Hamouda, Osamah; Eckert, Jana K; Neumann, Konrad; Kücherer, Claudia; Bartmeyer, Barbara; Poggensee, Gabriele; Oh, Nari; Pruss, Axel; Jessen, Heiko; Schumann, Ralf R Abstract Objectives: Toll-like receptors (TLRs) play an important role in the innate immune response to pathogens. TLR7 recognizes RNA of various viruses including HIV. The objective of this study…

This pathway is based on the figure 2 of Toll-like Receptors: Novel Pharmacological Targets for the Treatment of Neurological Diseases and figure 2 of Toll-like receptor and its roles in myocardial ischemic/reperfusion injury (see bibliography). The Toll-like receptors are used by mammals to recognize pathogen-associated molecules such as the cell wall components. The activation of TLR4 causes a cells inability to produce TNFa. TLR4 deals with MyD88 independent and dependent pathways, and due to LPS tolerant cells, inhibitors of the MyD88 dependent pathway are increased. TLR is important in the creation of protective immune responses to cancers, and the protection of brain tissue from injury. Proteins on this pathway have targeted assays available via the CPTAC Assay Portal ...

The innate immune system is the first line of defense against invading pathogens. Recognition of microbial ligands by the innate immune system relies on germ-line encoded, evolutionarily conserved receptors called pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are one such family of PRRs and are involved in innate defenses to a variety of microbes. At the core of TLR signaling pathways are Toll interleukin-1 receptor (TIR) domain containing adapter proteins. Much of the specificity of TLR pathways arise from the differential use of these adapter proteins. The TLR signaling cascade that ensues upon ligand recognition is marked by finely orchestrated molecular interactions between the receptor and the TIR domain containing adapter proteins, as well as various downstream kinases and effector molecules. Conserving the structural integrity of the TLR components is thus essential for maintaining a robust host defense system. Sometimes, changes in a protein can be brought about by single

Toll-like receptors are pattern recognition receptors that play a vital role in innate immunity pathways as they detect pathogen-associated molecular patterns on bacteria, fungi, protozoa, and viruses. Many TLRs are expressed on the plasma membrane while TLR7, TLR8, and TLR9 are expressed within the cell on the endosome. Upon activation, TLRs dimerize and bind to TIR-containing adaptor proteins including TRIF, TIRAP, TRAM, and MyD88. Downstream signaling through IKKs and the NFκB pathway results in the production of inflammatory cytokines and interferons.. Click on the poster below to view the interactive version.. ...

TLR 1 is a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system. TLR1 recognizes pathogen-associated molecular pattern with a specificity for gram-positive bacteria. TLR1 has also been designated as CD281 (cluster of differentiation 281). TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene. TLR1 recognises peptidoglycan and (triacyl) lipoproteins in concert with TLR2 (as a heterodimer). Toll-like receptors, ...

Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK. Source: KEGG:Toll-like Receptor Signaling ...

FREE FULLTEXT Lester, Richard T; Yao, Xiao-Dan; Ball, T Blake; McKinnon, Lyle R; Kaul, Rupert; Wachihi, Charles; Jaoko, Walter; Plummer, Francis A; Rosenthal, Kenneth L Free Access Article Outline Abstract Objectives: Toll-like receptors (TLR) are important in pathogen recognition and may play a role in HIV disease. We evaluated the effect of chronic untreated and…

Dr. Modlins lab is interested in the immunology of microbial infection. Infectious disease poses a major health problem worldwide. Essential to control of these diseases is the elucidation of immune mechanisms that result in resistance versus susceptibility to infection. The laboratorys focus is the identification of novel mechanisms by which the innate and adaptive immune system combat microbial pathogens. Using leprosy as a model, Dr. Modlins lab has made important contributions to our understanding of immunology including the role of mammalian Toll-like receptors and CD1-restricted T cells in host defense, including the cytokines pattens and antimicrobial pathways. These studies include 3 papers published in Nature and 10 in Science. It is hoped that the insights obtained from these studies will lead to better treatments and prevention of infectious diseases in humans.. ...

The recent discovery of an ancient family of toll-like receptors (TLRs) in the immune system has substantially enhanced the potential for a variety of therapies, for both failing immune systems, which leaves the body open to infection or over-active ones, which can lead to chronic inflammation. Signaling by Toll-Like Receptors provides a comprehensive review of important techniques in molecular biology, cell biology, biochemistry, genetics, and immunology and their critical application to the study of toll-like receptor structure, biological function, and the intracellular signaling triggered by these receptors, as well as the high promise for uncovering effective pharmaceutica ...

TY - JOUR. T1 - Toll-like receptor modulation in cardiovascular disease. T2 - A target for intervention?. AU - Földes, Gábor. AU - von Haehling, Stephan. AU - Anker, Stefan D.. PY - 2006/8. Y1 - 2006/8. N2 - Toll-like receptors (TLRs) form a family of pattern recognition receptors that have emerged as key mediators of innate immunity. These receptors sense invading microbes and initiate the immune response. TLR-mediated inflammation is an important pathogenic link between innate immunity and a diverse panel of clinical disorders. Among the processes in which TLRs play a role are cardiovascular disorders such as cardiac ischaemia, coronary artery disease, ventricular remodelling, cancer angiogenesis or transplant rejection. From these, many important opportunities for disease modification through TLR signalling manipulation can be imagined. Their role as potential targets for therapeutic intervention is just beginning to be appreciated and this article reviews the current status of these ...

Recent studies have demonstrated subset-specific roles for B cells in both aggravating and regulating the perturbations associated with obesity. Winer et al4 demonstrated that B-2 B cells promote insulin resistance and glucose intolerance through production of pathogenic antibodies. Additional studies have shown that sorted splenic B-2 B cells from obese mice secrete more IL-6 and MIP-2 and less IL-10 compared with lean controls,48 and circulating B cells (of which the vast majority are B-2) from patients with type 2 diabetes mellitus are also skewed toward a proinflammatory phenotype after toll-like receptor stimulation.49 Our adoptive transfers of B-2 B cells provide further evidence that B-2 B cells promote metabolic dysfunction during DIO. In contrast, B-1a B cells were recently shown to protect against the inflammatory and metabolic consequences of DIO through a combination of IgM and IL-10 production,50 and B-cell-derived IL-10 reduces adipose tissue inflammation and insulin resistance ...

The innate immune system detects highly conserved, relatively invariant structural motifs of pathogens. Toll-like receptors (TLRs) have been identified as the primary innate immune receptors. TLRs distinguish between different patterns of pathogens and activate a rapid innate immune response; however, TLRs can also be activated by host-derived molecules. In addition to being expressed in immune cells, TLRs are expressed in other tissues, such as those of the cardiovascular system. TLRs could, therefore, be a key link between cardiovascular disease development and the immune system. Indeed, evidence that TLR activation contributes to the development and progression of atherosclerosis, cardiac dysfunction in sepsis, and congestive heart failure, is convincing. Although much has been learned about TLR activation in cellular components of the cardiovascular system, the role individual TLR family members have in the pathophysiology of cardiovascular diseases and hence in clinical practice remains to be

Staff publications is the digital repository of Wageningen University & Research. Staff publications contains references to publications authored by Wageningen University staff from 1976 onward.. Publications authored by the staff of the Research Institutes are available from 1995 onwards.. Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.. We have a manual that explains all the features ...

Our gut is colonized by trillions of bacteria that do not activate the immune system because of careful compartmentalization. Such compartmentalization means that our immune system is ignorant of these microbes, and thus it has been proposed that loss of compartmentalization might result in an immune response to the colonizing bacteria. Microorganisms are sensed by cells that express pattern recognition receptors, such as Toll-like receptors, which recognize patterns specific to those microbes. Slack et al. show that Toll-like receptor-dependent signaling is required to maintain compartmentalization of bacteria to the gut of mice. In the absence of Toll-dependent signaling, intestinal bacteria disseminated throughout the body and the mice mounted a high-titer antibody response against them. This antibody response was of great functional importance because, despite the loss of systemic ignorance to intestinal microbes, the mice were tolerant of the bacteria. Thus, in the absence of innate ...

The immunosuppressive microenvironment in tumors hampers the induction of antitumor immunity by vaccines or immunotherapies. Toll-like receptor (TLR) ligands have the potential to treat tumors, but they can exert a mixture of positive and negative effects on inflammation in the tumor

Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK ...

Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK ...

We evaluated Toll-like receptor (TLR) function in primary human dendritic cells from 104 young (age 21C30) and older ( 65 years) individuals. dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in dendritic cells; notably, defects in cytokine production were strongly associated with poor antibody response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response. Introduction Aging is associated with a progressive decline in immune function (immunosenescence) resulting in increased susceptibility to viral and bacterial infections and decreased response to vaccines (1C3). Age-associated perturbations in the humoral and cell-mediated arms of the adaptive immune system are well documented (3, 4); however, the impact of aging on the innate immune system is less well defined. Age related deficiencies of the innate immune system are incompletely understood but ...

Toll-like receptors (TLRs) are in the front-line during the initiation of an innate immune response against invading pathogens. TLRs are type I transmembrane proteins that are expressed on the surface of immune system cells. They are evolutionarily conserved between insects and vertebrates. To date, 13 groups of mammalian TLRs have been identified, ten in humans and 13 in mice. They share a modular structure that consists of a leucine-rich repeat (LRR) ectodomain, a single transmembrane helix and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. Most TLRs have been shown to recognize pathogen-associated molecular patterns (PAMPs) from a wide range of invading agents and initiate intracellular signal transduction pathways to trigger expression of genes, the products of which can control innate immune responses. The TLR signaling pathways, however, must be under tight negative regulation to maintain immune balance because over-activation of immune responses in the body can cause autoimmune ...

to circumvent innate immunity was demonstrated (Cirl et al. 2008, Nature Medicine 14, 399-406). This involves a bacterial TIR domain-containing protein (Tcp) that is secreted by bacterial pathogens and inhibits Toll-like receptor (TLR) signalling. ,p, Toll-like receptors have a central role in innate immunity. They recognise molecules from microbial pathogens and trigger an immune response through a signalling domain called TIR. Bacterial Tcps contain a TIR domain that mimics the TIR domain of Toll-like receptors. TLR signalling is interrupted when MyD88, a downstream component of TLR signalling, binds to the TIR domain of a bacterial Tcp instead of to the TIR domain of a Toll-like receptor. This way, secreted Tcps impair the release of cytokines and, subsequently, prevent an inflammatory response. ,p, Our data show that bacterial Tcps or the TIR domains contained in Tcps can be used to modulate cytokine responses of innate immune cells as is desirable in the treatment of autoimmune diseases. ...

Decline in immune function is a hallmark of aging, leading to increased susceptibility of elderly individuals to bacterial infections of lungs, urinary tract, skin and soft tissues and reactivation of inactive tuberculosis and herpes zoster (reviewed in Refs. 1 and 2). There is an increased severity of pneumococcal, influenza, and respiratory syncytial viral infections in the elderly population (3, 4, 5, 6). For example, an estimated 90% of the 20,000 deaths that are attributed to influenza annually in the U.S. occur in persons aged ≥65 years (7). Age-related changes in the adaptive immune system are well-documented and include diminished and/or altered cytokine patterns, reduction in clonal expansion and function of Ag-specific T and B cells and a decline in Ag-presenting cell function (1, 2, 8, 9). The decline in adaptive immune function leads to decreased efficacy of preventive vaccination in the elderly. In the case of influenza, although the vaccine is ∼70-90% effective in preventing ...

Plants perceive microbial pathogens though cell-surface receptors that recognize conserved microbial patterns such as flagellin. Previous studies have…

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Genital inflammation is associated with increased HIV acquisition risk. Induction of an inflammatory response can occur through the recognition of pathogenic or commensal microbes by Toll-like receptors (TLRs) on various immune cells. We used a in vitro peripheral blood mononuclear cell (PBMC) system to understand the contribution of TLR stimulation in inducing inflammation and the activation of target T cells, and its effect on HIV susceptibility. PBMCs were stimulated with TLR agonists LPS (TLR4), R848 (TLR7/8), and Pam3CSK4 (TLR1/2), and then infected with HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines in cell culture supernatants. Flow cytometry was used to measure the activation state (CD38 and HLA-DR), and CCR5 expression on CD4+ and CD8+ T cells. Although TLR agonists induced higher cytokine and chemokine secretion, they did not significantly activate CD4+ and CD8+ T cells and showed decreased CCR5 expression relative to the unstimulated control. Despite several classes of

Atherosclerosis is an inflammatory disease with a strong involvement of innate immunity. Toll-like receptors (TLRs) are the best-characterized pattern recognition receptors of the innate immune system. Almost all cell types in lesions, inflammatory leukocytes and resident vascular cells alike express TLRs. TLRs are able to sense modified lipids, enhance foam cell formation, induce leukocyte recruitment, and increase cytokine and matrix metalloproteinase production within atherosclerotic lesions. As such, TLRs represent an important link between atheroma and inflammation, making them attractive targets for the treatment of cardiovascular disease. Novel TLR-specific biologics are being developed and tested in other inflammatory diseases. This article will describe the exciting potential of TLRs as therapeutic targets for the treatment of atherosclerosis and will also highlight the potential challenges in the clinical application of TLR-based therapeutics in cardiovascular disease.

As we learn more about the biology of the Toll-like receptors (TLRs), a wide range of molecules that can activate this fascinating family of pattern recognition receptors emerges. In addition to conserved pathogenic components, endogenous danger signals created upon tissue damage are also sensed by TLRs. Detection of these types of stimuli results in TLR mediated inflammation that is vital to fight pathogenic invasion and drive tissue repair. Aberrant activation of TLRs by pathogenic and endogenous ligands has also been linked with the pathogenesis of an increasing number of infectious and autoimmune diseases, respectively. Most recently, allergen activation of TLRs has also been described, creating a third broad class of TLR stimulus that has helped to shed light on the pathogenesis of allergic disease. To date, microbial activation of TLRs remains best characterized. Each member of the TLR family senses a specific subset of pathogenic ligands, pathogen associated molecular patterns (PAMPS), and a

Toll-like receptors (TLRs) have been described as sensors for pathogen-associated molecular patterns crucial for the initiation of an innate immune response. These mechanisms were developed long before the adaptive immune system evolved. The latest additions to the growing list of TLR ligands are he …

This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR) modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful) contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field.

Allergic disorders, such as asthma, are symptomatic reactions of the immune system to common and innocuous environmental antigens. These inflammatory disorders are caused by aberrant immune regulation in which various signalling receptors are involved. Pathogen recognition receptors like the TLRs and NLRs families of receptors are one of the key components of the innate immune system. The function of these receptors has been linked with susceptibility towards the development of allergic diseases, including asthma, making the TLRs and NLRs good targets for novel effective therapies of allergic diseases. In this study the mRNA expression levels of different TLRs and NLRs in the lung tissue in mild and severe mouse models of allergic asthma were measured by q-PCR. In addition, broncho-alveolar lavage fluid (BALF) was collected and cell numbers analysed. In the mild and severe asthma models different TLR and NLR mRNA expression profiles are observed. In the severe asthma model, a higher cell influx ...

El Kasmi, K.C., J.E. Qualls, J.T. Pesce, A.M. Smith, R.W. Thompson, M. Henao-Tamayo, R.J. Basaraba, T. Konig, U. Schleicher, M.S. Koo, G. Kaplan, K.A. Fitzgerald, E.I. Tuomanen, I.M. Orme, T.D. Kanneganti, C. Bogdan, T.A. Wynn, and P.J. Murray. 2008. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9:1399-1406 ...

Statins enhance toll-like receptor 4-mediated cytokine gene expression in astrocytes: implication of Rho proteins in negative feedback regulation.: Toll-like re

Toll-like receptors (TLRs) expressed by antigen-presenting cells of the innate immune system, such as macrophages, detect microbial products and activate signalling cascades that initiate specific gene expression programmes that define the subsequent adaptive immune response. However, it is poorly understood how TLR-specific responses arise, as many of the signalling components are common to multiple TLRs, and it is likely that as yet undiscovered phosphorylations of signalling proteins contribute to specificity of TLR pathways. TLR4, the receptor for lipopolysaccharide (LPS), is used as a model system for TLR signalling, as it activates many of the signalling mechanisms utilised by other TLRs, and I attempted to discover novel regulatory phosphorylations in LPS-activated RAW 264.7 macrophages. Because it is not yet possible to accurately predict post-translational modifications from genomic data, the exact sites of phosphorylation have to be identified experimentally, and the method of choice ...

TY - JOUR. T1 - Signatures of balancing selection in toll-like receptor (TLRs) genes - novel insights from a free-living rodent. AU - Kloch, Agnieszka. AU - Wenzel, Marius A.. AU - Laetsch, Dominik R.. AU - Michalski, Olek. AU - Bajer, Anna AU - Behnke, Jerzy M.. AU - Welc-Falȩciak, Renata. AU - Piertney, Stuart B.. N1 - Correction to: Scientific Reports https://doi.org/10.1038/s41598-018-26672-2, published online 30 May 2018 The work was supported by grant no. DEC-2012/07/B/NZ8/00058 from the Polish National Science Centre to A.K. Field studies were funded by grant MNiI 2P04C09827 „Badania naturalnych źródeł zarażenia mikropasożytów patogennych dla człowieka to AB. We are thankful to Dr. hab W. Babik who provided access to an Illumina MiSeq platform, and to K. Dudek who prepared the Nextera library. Special thanks to A. Biedrzycka for her valuable comments on the final version of the manuscript. We also would like to thank two anonymous reviewers for their valuable comments that ...

...Washington D.C. -- Blocking signals from a key molecular receptor t...David J. Hackam and his laboratory team at the Childrens Hospital of P...Toll-like receptors are key players in the innate immune system. Protr...But Hackams group found that the stresses of oxygen deprivation and bo...,Leading,cause,of,death,in,preemies,might,be,controlled,by,resetting,a,molecular,switch,biological,biology news articles,biology news today,latest biology news,current biology news,biology newsletters

Fli-l is a member of the Ets family of transcription factors whose role has been defined in a variety of cellular populations. It plays a role in the development and function of a wide array of immune cells, and plays a critical role in the development of endothelial cells. Fli-l has also been implicated in the pathogenesis of SLE; patients with SLE expressed significantly higher levels of Fli-l in their peripheral blood lymphocytes than did healthy patients, and murine models of SLE, such as the MRLllpr model, also expressed higher levels of Fli-l in their peripheral blood lymphocytes than did normal strains of mice. Conclusive evidence linking Fli-l overexpression to SLE development was shown in a transgenic mouse model, where 2-3 fold overexpression of Fli-l resulted in the development of an autoimmune disease similar to SLE. Currently, Fli-l s possible roles in the innate immune response have not been explored. This study aimed to identify possible roles for Fli-l in the innate immune ...

Toll-like Receptors (TLRs) are not only crucial for the initiation of immune response, but also play a key role in several inflammatory diseases. This..

Toll-like receptor 9 (TLR9), a naturally existing immune regulatory site, not only takes part in enhancing anti-tumor immunity but also promoting the ..

Toll-like receptors (TLRs) are pattern-recognition receptors that have a pivotal role as primary sensors of microbial products and as initiators of innate and adaptive immune responses. We investigated the role of TLR2, TLR3, and TLR4 activation during cutaneous allergen sensitization in the modulation of allergic asthma. The results show that dermal exposure to TLR4 ligand lipopolysaccharide (LPS) or TLR2 ligand Pam3Cys suppresses asthmatic responses by reducing airway hyperreactivity, mucus production, Th2-type inflammation in the lungs, and IgE antibodies in serum in a dose-dependent manner. In contrast, TLR3 ligand Poly(I:C) did not protect the mice from asthmatic symptoms but reduced IgE and induced IgG2a in serum. LPS (especially) and Pam3Cys enhanced the activation of dermal dendritic cell (DCs) by increasing the expression of CD80 and CD86 but decreased DC numbers in draining lymph nodes at early time points. Later, these changes in DCs led to an increased number of CD8(+) T cells and enhanced

Production of type I IFNs is critical to the host immune defense against viral infection and is a hallmark of virally infected cells. Induction of antiviral IFN responses can also occur as a result of TLR3/4 ligand stimulation. Although virtually all cell types can elicit an IFN response during viral infection, expression of TLRs is more restricted to immune cells and, thus, TLR-induced antiviral responses may be primarily important in these cell types. As the pathways involved in TLR3/4-induced type I IFN production are being carefully studied, an interesting question remains unanswered regarding the role of these pathways and signaling mediators during viral infections. In this work, we compare the role of the kinase TBK1 in IFN responses induced by LPS, polyI:C, and SeV. We have found a requirement for TBK1 in IRF3 activation and IFNβ production in response to LPS and polyI:C. However, during infection with SeV, we have found a cell type-dependent requirement for TBK1 for induction of IFN ...

TY - JOUR. T1 - A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. AU - Datta, Sandip K.. AU - Redecke, Vanessa. AU - Prilliman, Kiley R.. AU - Takabayashi, Kenji. AU - Corr, Maripat. AU - Tallant, Thomas. AU - DiDonato, Joseph. AU - Dziarski, Roman. AU - Akira, Shizuo. AU - Schoenberger, Stephen P.. AU - Raz, Eyal. PY - 2003/4/15. Y1 - 2003/4/15. N2 - Dendritic cells (DCs) are capable of cross-presenting exogenous Ag to CD8+ CTLs. Detection of microbial products by Toll-like receptors (TLRs) leads to activation of DCs and subsequent orchestration of an adaptive immune response. We hypothesized that microbial TLR ligands could activate DCs to cross-present Ag to CTLs. Using DCs and CTLs in an in vitro cross- presentation system, we show that a subset of microbial TLR ligands, namely ligands of TLR3 (poly(inosinic-cytidylic) acid) and TLR9 (immunostimulatory CpG DNA), induces cross-presentation. In contrast to presentation of Ag to CD4+ T ...

In the past ten years, studies have shown the recognition of |i |Trypanosoma cruzi|/i|-associated molecular patterns by members of the Toll-like receptor (TLR) family and demonstrated the crucial participation of different TLRs during the experimental infection with this parasite. In the present review, we will focus on the role of TLR-activated pathways in the modulation of both innate and acquired immune responses to |i |T. cruzi|/i| infection, as well as discuss the state of the art of vaccine research and development against the causative agent of Chagas disease (or American trypanosomiasis).

Inflammation of the uterus and oviduct is associated with reduced reproductive performance in humans and domestic animals. Toll-like receptors are expressed in various immune and non-immune cells and play a crucial role in innate immunity. Toll-like receptor e 4 (TLR4) can detect lipopolysaccharide (LPS) from Gram-negative bacteria leading to the secretion of pro-inflammatory cytokines, chemokines, antimicrobial peptides and other inflammatory mediators. To investigate the effects of a local inflammation on the expression levels of TLR4 and pro-inflammatory cytokines, 12 female rabbits received an intracervical infusion with either saline solution endotoxin-free (carrier, 2 mL; n ¼ 6) or LPS (500 mg diluted in 2 mL of saline solution; n ¼ 6). Blood samples were performed at 0, 30, 60 and 90 min and 2,4,6 and 24 h after treatment to evaluate interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) plasma concentrations.. ...

The Drosophila Toll receptor does not interact directly with microbial determinants, but is instead activated by a cleaved form of the cytokine-like molecule Spätzle. During the immune response, Spätzle is processed by complex cascades of serine proteases, which are activated by secreted pattern-recognition receptors. Here, we demonstrate the essential role of ModSP, a modular serine protease, in the activation of the Toll pathway by gram-positive bacteria and fungi. Our analysis shows that ModSP integrates signals originating from the circulating recognition molecules GNBP3 and PGRP-SA and connects them to the Grass-SPE-Spätzle extracellular pathway upstream of the Toll receptor. It also reveals the conserved role of modular serine proteases in the activation of insect immune reactions. Buchon, Nicolas; Poidevin, Mickael; Kwon, Hyun-Mi; Guillou, Aurélien; Sottas, Valentin; Lee, Bok-Luel; Lemaitre, Bruno

Toll Like Receptor Family (TLR) - Drugs in Development, 2021 provides in depth analysis on Toll Like Receptor Family (TLR) targeted pipeline therapeutics. The report provides comprehensive information complete with Analysis by Indications, Stage of Development, Mechanism of Action (MoA), Route of Administration (RoA) and Molecule Type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in Toll Like Receptor Family (TLR) targeted therapeutics development and features dormant and discontinued projects. The report analyses the pipeline products across relevant therapy areas under development targeting Toll Like Receptor Family (TLR).. The report helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies ...

Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. Interested in the mechanism by which lipopolysacchride (LPS) activates mammalian immune cells, Beutler identified the LPS receptor. Identification of the receptor hinged on the positional cloning (a method of gene identification) of the mammalian Lps locus, which had been known since the 1960s as a key gene for biological responses to LPS.[4]. Beutler thus discovered the key sensors of microbial infection in mammals. He found that one of the mammalian toll-like receptors,[5] TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex.[6] The TLRs work in the perception of microbes. Ten are now known in humans. Each detects signature molecules produced early in an infection. These receptors also work in severe illness, including shock and systemic inflammation as it occurs in the course of an infection. They are also active in sterile inflammatory and autoimmune ...

miRs (microRNAs) post-transcriptionally regulate gene expression mainly by repressing translation or by inducing mRNA degradation. Dicer, an enzyme responsible for miR biogenesis, is required for T-cell function, suggesting regulatory roles for miRs in lymphocytes. However, specific roles for individual miRs are only just beginning to emerge. miR-155 is encoded within an exon of the non-coding RNA known as bic (B-cell integration cluster) and high levels of bic expression are induced upon antigen receptor stimulation of B- and T-cells, as well as TLR (Toll-like receptor) stimulation of macrophages and dendritic cells. High levels of bic/miR-155 are found in B-cell lymphomas and solid tumours, indicating that this locus may also be linked to cancer. Indeed, transgenic mice overexpressing miR-155 develop B-cell malignancies. To define the in vivo role of bic/miR-155 (bic), we have studied bic-deficient mice. These mice are immunodeficient and fail to generate high levels of class-switched antibody upon

Toll-like receptors (TLRs) perform a vital role in disease resistance through their recognition of pathogen associated molecular patterns (PAMPs). Recent advances in genomics allow comparison of TLR genes within and between many species. This study takes advantage of the recently sequenced chicken genome to determine the complete chicken TLR repertoire and place it in context of vertebrate genomic evolution. The chicken TLR repertoire consists of ten genes. Phylogenetic analyses show that six of these genes have orthologs in mammals and fish, while one is only shared by fish and three appear to be unique to birds. Furthermore the phylogeny shows that TLR1-like genes arose independently in fish, birds and mammals from an ancestral gene also shared by TLR6 and TLR10. All other TLRs were already present prior to the divergence of major vertebrate lineages 550 Mya (million years ago) and have since been lost in certain lineages. Phylogenetic analysis shows the absence of TLRs 8 and 9 in chicken to be the

Dr Andrew Thorley is a Lecturer in the Lung Cell Biology Group at the National Heart and Lung Institute with a research focus on nanotechnology and pulmonary innate immunity. Dr Thorley also teaches on a number of undergraduate Medicine, Biomedical Science, and Engineering courses.. Dr Thorley graduated from the University of Bath in 2000 with a Masters in Pharmacology. During his undergraduate study, he spent a year working for Bayer plc investigating the role of matrix metalloproteinases in pulmonary alveolar macrophage-mediated inflammation and tissue remodelling. He subsequently joined Professor Tetleys Lung Cell Biology group at the National Heart and Lung Institute to undertake a PhD investigating the role of alveolar macrophages, dendritic cells, and respiratory epithelial cells in lung inflammation, with a particular focus on Toll-like receptor activation and bacterial infection.. Dr Thorley has continued his research at Imperial College by developing his work on Toll-like receptors, ...

Title:Toll-Like Receptors in Human Multiple Myeloma: New Insight into Inflammation-Related Pathogenesis. VOLUME: 14 ISSUE: 4. Author(s):J. Abdi, J. Garssen and F. Redegeld. Affiliation:Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.. Keywords:Bone marrow, drug resistance, inflammation, multiple myeloma, toll like receptors.. Abstract:Multiple myeloma (MM) is a clonal neoplasm characterized by expansion of malignant plasma cells in the bone marrow causing various complications including osteolytic lesions and impaired immune function. It has recently been reported that human myeloma cells express multiple Toll-like receptors (TLRs), and their activation-induced functional responses show heterogeneity among cell lines and patient samples. TLRs are critical germ-line encoded molecules expressed in immune cells as well as in a variety of cancer cells. In multiple myeloma, they may ...

Toll-like receptor family (TLR) has a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. TLRs recognize pathogen-associated molecular patterns (PAMP) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. Toll-like receptor 4 (TLR4) cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). TLR4 acts via MYD88, TIRAP and TRAF6 to lead to NFkB activation, cytokine secretion and inflammatory response. TLR4 is highly expressed in placenta, spleen and peripheral blood leukocytes. Genetic variation in TLR4 is associated with age-related macular degeneration 10 (ARMD10), an irreversible vision loss.. ...

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases. It is characterized by chronic inflammation of the joint leading to its destruction. Although the initiating cause remains elusive, environmental factors and genetic background are known to contribute to the etiology of RA. The role of Toll-like receptors (TLRs) in innate immunity and their ability to recognize microbial products has been well characterized. TLRs are able to recognize endogenous molecules released upon cell damage and necrosis, and are present in RA synovial fluid. Although it appears unlikely that a pathogen underlies the pathogenesis or progression of RA, the release of endogenous TLR ligands during inflammation may activate TLRs and perpetuate the disease. An increasing body of circumstantial evidence implicates TLR signaling in RA, although, at present, their involvement is not defined comprehensively. Targeting individual TLRs or their signaling transducers may provide a more specific therapy ...

TY - JOUR. T1 - Toll-like receptor 4 is involved in titanium dioxide nanoparticle incorporation into cells. AU - Mano, Sharmy Saimon. AU - Kanehira, Koki. AU - Sonezaki, Shuji. AU - Taniguchi, Akiyoshi. PY - 2014/7. Y1 - 2014/7. N2 - The innate immune system is important for defense against foreign pathogens, such as bacteria and viruses. We hypothesized that the innate immune system is also important for the interaction between cells and nanomaterials, because cells do not have a specific defense system for nanomaterials. In this study, we demonstrated the effect of Toll-Like Receptor 4 (TLR 4), which is an important molecule for the innate immune system, on the uptake of TiO2 nanoparticles (NPs). The results indicated that TLR 4 expression vector-transfected cells increased the uptake of TiO2 NPs and also increased IL-6 mRNA induction by TiO2 NP exposure. Modifying TiO2 NPs with polyethylene glycol (PEG) reduced their uptake and inflammatory-signal transduction via TLR 4. Our results suggest ...

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TY - JOUR. T1 - Toll-like Receptor 9 Signaling Is Augmented in Systemic Sclerosis and Elicits Transforming Growth Factor β-Dependent Fibroblast Activation. AU - Fang, Feng. AU - Goncalves Marangoni, Roberta. AU - Zhou, Xingchun. AU - Yang, Yang. AU - Ye, Boping. AU - Shangguang, Anna. AU - Qin, Wenjie. AU - Wang, Wenxia. AU - Bhattacharyya, Swati. AU - Wei, Jun. AU - Tourtellotte, Warren G.. AU - Varga, John. PY - 2016/8/1. Y1 - 2016/8/1. N2 - Objective: Although transforming growth factor β (TGFβ) is recognized as being a key trigger of fibroblast activation in systemic sclerosis (SSc), prominent innate immunity suggests that additional pathways contribute to disease persistence. Toll-like receptor 9 (TLR9) is implicated in autoimmunity and fibrosis; however, the expression, mechanism of action, and pathogenic role of TLR9 signaling in SSc remain uncharacterized. The aim of this study was to explore the expression, activity, and potential pathogenic role of TLR9 in the context of skin ...

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Crosslinking of regulatory immunoreceptors (RR), such as BDCA-2 (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses production of type-I interferon (IFN)-α/β and other cytokines in response to Toll-like receptor (TLR) 7/9 ligands. This cytokine-inhibitory pathway is mediated by spleen tyrosine kinase (Syk) associated with the ITAM-containing adapter of RR. Here we demonstrate by pharmacological targeting of Syk that in addition to the negative regulation of TLR7/9 signaling via RR, Syk also positively regulates the TLR7/9 pathway in human pDCs. Novel highly specific Syk inhibitor AB8779 suppressed IFN-α, TNF-α and IL-6 production induced by TLR7/9 agonists in primary pDCs and in the pDC cell line GEN2.2. Triggering of TLR9 or RR signaling induced a differential kinetics of phosphorylation at Y352 and Y525/526 of Syk and a differential sensitivity to AB8779. Consistent with the different roles of Syk in TLR7/9 and RR signaling, a concentration of AB8779 ...

Mitochondria, known to share many common features with prokaryotic cells, accumulate several endogenous ligands of the pattern-recognition Toll-like receptor 4 (TLR4), such as the heat shock proteins (Hsp) 70 and 60. TLR4 specifically recognises and responds to LPS of Gram-negative bacteria and participates in both autoimmune reactions and tissue regeneration due to its ability to recognise endogenous ligands. In the present study we show that mitochondria extracts obtained from hydrogen peroxide-dysfunctionalised cells induce a pro-inflammatory response in human THP-1 myeloid leukaemia cells. This inflammatory response was similar to that caused by LPS and much stronger than that induced by the extracts of normal mitochondria. Such reactions include activation of stress-adaptation hypoxia-inducible factor 1 alpha (HIF-1?) and expression/release of the pro-inflammatory cytokines IL-6 and TNF-?. Pre-treatment of THP-1 myeloid macrophages with TLR4-neutralising antibody before exposure to ...

Dysregulated lipid metabolism and inflammation are linked to the development of insulin resistance in obesity, and the intracellular accumulation of the sphingolipid ceramide has been implicated in these processes. Here, we explored the role of circulating ceramide on the pathogenesis of insulin resistance. Ceramide transported in LDL is elevated in the plasma of obese patients with type 2 diabetes and correlated with insulin resistance but not with the degree of obesity. Treating cultured myotubes with LDL containing ceramide promoted ceramide accrual in cells and was accompanied by reduced insulin-stimulated glucose uptake, Akt phosphorylation, and GLUT4 translocation compared with LDL deficient in ceramide. LDL-ceramide induced a proinflammatory response in cultured macrophages via toll-like receptor-dependent and -independent mechanisms. Finally, infusing LDL-ceramide into lean mice reduced insulin-stimulated glucose uptake, and this was due to impaired insulin action specifically in ...

Chronic Lymphocytic Leukaemia (CLL) development and progression is thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR), and environmental signals for survival and expansion including Toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either pro-survival BTK/PI3K/AKT-mediated, or pro-apoptotic p38MAPK-mediated signaling pathways, whilst sIgM ligation predominantly engages the ...

Toll-like receptors (TLRs) on T cells can modulate their responses, however, the extent and significance of TLR expression by lung T cells, NK cells, or NKT cells in chronic obstructive pulmonary disease (COPD) is unknown. Lung tissue collected from clinically-indicated resections (n = 34) was used either: (a) to compare the expression of TLR1, TLR2, TLR2/1, TLR3, TLR4, TLR5, TLR6 and TLR9 on lung CD8+ T cells, CD4+ T cells, NK cells and NKT cells from smokers with or without COPD; or (b) to isolate CD8+ T cells for culture with anti-CD3ε without or with various TLR ligands. We measured protein expression of IFN-γ, TNF-α, IL-13, perforin, granzyme A, granzyme B, soluble FasL, CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL9 in supernatants. All the lung subsets analyzed demonstrated low levels of specific TLR expression, but the percentage of CD8+ T cells expressing TLR1, TLR2, TLR4, TLR6 and TLR2/1 was significantly increased in COPD subjects relative to those without COPD. In contrast, from the same

purpose. Evidence from genetic-association studies in conjunction with the demonstration of complement deposition in the retina and choroid implicates noncellular pathways of innate immunity in the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine whether common variation in the 10 human toll-like receptors (TLRs) alters the risk of AMD.. methods. Sixty-eight SNPs were iteratively genotyped across the TLR genes in a cohort of 577 subjects, with and without AMD. Two additional cohorts were used for replication studies. Standard genetic-association methods were used to analyze the results for association with disease and interaction with other loci.. results. Coding SNPs in TLR3 (rs3775291) and TLR7 (rs179008) showed association with AMD in one group (P = 0.01 and P = 0.02, respectively) before correction for multiple testing. For both SNPs, the association with AMD arose due to an excess of heterozygotes compared with homozygotes for the major ...

The innate immune response elicited by activation of TLRs (Toll-like receptors) plays an important role in the pathogenesis of atherosclerosis. We hypothesized that cardiovascular risk factors are associated with the activation status of the innate immune system. We therefore assessed the responsiveness of TLRs on circulating cells in two groups of patients with established atherosclerosis and related this to the presence of cardiovascular risk factors. TNF (tumour necrosis factor)-α release induced by TLR2 and TLR4 activation was measured in patients with established coronary [PCI (percutaneous coronary intervention) study, n=78] or carotid artery disease [CEA (carotid endarterectomy) study, n=104], by stimulating whole blood samples with lipopolysaccharide (TLR4 ligand) and Pam3CSK4 [tripalmitoylcysteinylseryl-(lysyl)4; TLR2 ligand]. As an early activation marker, CD11b expression was measured by flow cytometry on CD14+ cells. Obesity was the only risk factor that correlated with the TLR ...

Toll-like receptor 2 also known as TLR2 is a protein that in humans is encoded by the TLR2 gene. TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR2 is one of the toll-like receptors and plays a role in the immune system. TLR2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system. The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most ...

Toll-like receptor 9 (TLR9) often known as CD289 (cluster of differentiation 289), is a member of the Toll-like receptor family that recognizes pathogen

Toll-like receptor 9 (TLR9) often known as CD289 (cluster of differentiation 289), is a member of the Toll-like receptor family that recognizes pathogen

Plant cell wall is the most abundant biomaterial on earth and consists of a matrix of cellulose and other polymers, primarily hemicellulose and lignin. These polymers confer to the plant cell wall resistance to degradation, which also makes these materials a challenge to use as substrates in many industrial applications worldwide. The potential is enormous both for the nutrition industry and for biofuel production. The conversion of the plant cell wall polysaccharides into soluble utilizable sugars can be performed by several microorganisms, for which their developed enzymatic systems play a major role in recycling plant cell wall fixed carbon. These microorganisms, of considerable biotechnological importance, have evolved modular enzymes, in which the catalytic modules are appended to non-catalytic modules, designated carbohydrate-binding modules (CBM). Profound knowledge about specificity of the different CBM families will bring a relevant contribution to the possible engineering of more ...

Background: Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. TLR2 is a member of the TLR family, and has been shown to recognize not only foreign substances, but also endogenous ligands, which induce inflammatory response called homeostatic inflammation. Recently, homeostatic inflammation has been revealed to contribute to the pathophysiology of various diseases. However, the role of homeostatic inflammation mediated by TLR2 on pressure overload-induced cardiac hypertrophy remains unclear.. Methods and Results: Pressure overload was induced in 8- to 12-week-old wild-type (WT) and TLR2 knock-out (KO) mice by transverse aortic constriction (TAC). In WT mice, TLR2 mRNA expression at 2 weeks after TAC was up-regulated compared with that after sham operation (1.32±0.18 versus 0.50±0.03, n=4, p=0.004). At 2 weeks after TAC, KO mice showed reduced cardiac hypertrophy and fibrosis with more left ventricular dilatation and impaired systolic function ...

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Seminal research over the past 20 years has revealed atherosclerosis to be a chronic inflammatory process that shares features with traditional inflammatory diseases including rheumatoid arthritis. More recently, emphasis has been placed on the role of innate immunity in the development and progression of atherosclerosis. In particular, pattern recognition receptors, including Toll-like receptors (TLRs), have been the focus of much attention as modulators of atherogenesis. This review provides an update on the developments in this area of research in the past 2 years, with a specific focus on the current controversies and how these may affect the design of therapeutics. Specifically, we will address the recent evidence that TLRs elicit both protective and detrimental effects in atherosclerosis and the emerging observation that the outcome of TLR signaling is dependent on the agonist and responding cell type.

Pattern recognition receptors, including the Toll-like receptors (TLRs), are important in the induction and activation of two critical arms of the host defence to pathogens and microorganisms; the rapid innate immune response (as characterised by the production of Th1 promoting cytokines and type 1 interferons) and the adaptive immune response. Through this activation, ligands and agonists of TLRs can enhance immunotherapeutic efficacy. Resiquimod is a small (water-soluble) agonist of the endosome-located Toll-like receptors 7 and 8 (TLR7/8). However due to its molecular attributes it rapidly distributes throughout the body after injection. To circumvent this, these TLR agonists can be incorporated within delivery systems, such as liposomes, to promote the co-delivery of both antigen and agonists to antigen presenting cells. In this present study, resiquimod has been chemically conjugated to a lipid to form a lipid-TLR7/8 agonist conjugate which can be incorporated within immunogenic cationic ...

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Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs.

In the present study, we introduced robust assays to monitor the endogenous IRAK4 and IRAK1 activities in cell extracts, which have permitted these protein kinase activities to be studied independently of one another for the first time. Establishing these assays has provided new insights into the mechanisms by which IRAKs 1 and 4 are activated. We found that IRAK4 is constitutively active and its activity was not increased when the MyD88 signalling network is switched on. Our results show that the agonist-dependent trans-autophosphorylation of IRAK4 at Thr345 and Ser346 is not a measure of IRAK4 activity, but is a consequence of the dimerization of IRAK4 triggered by its interaction with MyD88. Moreover, although IL-1-stimulaion converts IRAK1 from an inactive into an active form, the activation of IRAK1 does not require IRAK4 activity, or the phosphorylation or ubiquitylation of IRAK1. It would therefore appear that IRAK1 is activated when it interacts with IRAK4, perhaps by IRAK4-induced IRAK1 ...

TY - JOUR. T1 - Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation. AU - van den Ancker, W.. AU - van Luijn, M.M.. AU - Ruben, J.M.. AU - Westers, T.M.. AU - Bontkes, H.J.. AU - Ossenkoppele, G.J.. AU - de Gruijl, T.D.. AU - van de Loosdrecht, A.A.. PY - 2011. Y1 - 2011. U2 - 10.1007/s00262-010-0917-y. DO - 10.1007/s00262-010-0917-y. M3 - Article. C2 - 20859626. VL - 60. SP - 37. EP - 47. JO - Cancer Immunology and Immunotherapy. JF - Cancer Immunology and Immunotherapy. SN - 0340-7004. IS - 1. ER - ...

Numerous studies have reported that engagement of TLR proteins leads to the activation of NF-κB and MAP kinases. These activation events are elicited upon engagement of TLR2, TLR4, and TLR9 by their distinct agonists,9 12 21 suggesting that they are shared responses that use a common signal transduction pathway. This pathway is likely to be mediated by MyD88, and the downstream signalling components IL1 receptor associated kinases and TRAF6 (reviewed by Means et al 2 and ONeill and Greene7). Published studies have shown that engagement of TLR4, but not TLR2 and TLR9, can also lead to the activation of an MyD88 independent pathway and then to NF-κB and MAP kinase activation.26 27 Together, these reports show that TLR proteins use both shared and unique signal transduction pathways. Here we have extended these findings by identifying a cellular response that is induced by different TLR agonists, and a distinct response that is restricted to specific TLR proteins. Specifically, both TLR2 and ...

The zebrafish genomic sequence database was analysed for the presence of genes encoding members of the Toll-like receptors (TLR) and interleukin receptors (IL-R) and associated adaptor proteins containing a TIR domain. The resulting predictions show the presence of one or more counterparts for the human TLR1, TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, IL-1R and IL-18R genes and one copy of the adaptor genes MyD88, MAL, TRIF and SARM. In contrast to data for the pufferfish Fugu rubripes, zebrafish has two genes that are highly similar to human TLR4. In addition, one fish-specific TLR group can be distinguished that is closely related to the Drosophila melanogaster Toll-9 gene. The sequence of cloned cDNAs for TLR4, TLR2 and MyD88 show the same intron-exon organisation as in the human counterparts. Expression analysis using reverse transcriptase-PCR (RT-PCR) shows that 17 of the predicted zebrafish TLR genes and all the genes encoding adaptor proteins are expressed in the adult stage. A subset of ...

Research proven purified goat polyclonal TLR-3 (Toll-like receptor3)/CD283 antibody. Designed for immune response research. Excellent for western blotting, DIRECT Elisa and related applications.

As the senior author of the paper yall you are discussing first off I am honored that Caryn and others have commented on our work and findings-this certainly makes a basic scientist feel good that our work may have some real life implications. Secondly, hopefully to clarify, we were able to induce PE-like symptoms in rats by excessively activating the moms immune system during pregnancy. As Caryn mentioned in somewhat other terms, the moms immune system is already activated trying to prepare for and accept a half-foreign fetus. This represents a pro-inflammatory state in preparation for these events. What we showed that is that the events associated with pregnancy do not cause PE alone, nor does immune system activation in non-pregnant animals, but the combination of the 2 caused PE like symptoms in animals. Toll-like receptor 3 senses double-stranded RNA (which are rotavirus and rheovirus), but several other factors can activate these receptors during pregnancy. While I would love to prove ...

Toll-like receptor 4 in bone marrow-derived cells as well as tissue-resident cells participate in aggravating autoimmune destructive arthritis ...

Clinical researchers will determine whether an experimental vaccine can successfully stimulate the immune system in patients following treatment for brain tumor to prevent its recurrence.. Conventional malignant brain tumor (glioma) therapy, consisting of surgical removal, followed by radiation and chemotherapy, rarely lengthens a patients life for more than two years. While these treatments help kill cancerous cells composing the brain tumor mass, individual cancer cells that have already infiltrated brain tissue in many other brain areas live on and eventually produce widespread tumor recurrence in the brain. Evidence indicates that a patients innate immune cells, called dendritic cells, initially recognize a tumors antigens (peptides) that are found on the cancer cells surface. But, the cancer cells send out signals that silence the dendritic cells before they can summon adaptive immune cells that have been taught to recognize and kill those specific antigens. Scientists, therefore, ...

Originally aired on October 31, 2016 • 1:00 PM ET • Hosted by Community of Basic Scientists Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression Speaker: Jeffrey Rathmell, PhD • Vanderbilt University School of Medicine Moderator: Xunrong Luo, MD, PhD • Northwestern University