Toll-like Receptors and Cancer

This paper presents a study of the flow of ice in wedge-shaped converging channels. Such flows are encountered in the relatively constricted waters of the Canadian Arctic Archipelago. Ridging, lead opening patterns, development of a highpressure area, and arch formation are some of the processes which take place during ice flow through converging channels. An idealized geometry and steady wind forcing were used in the testing. The results give ice cover velocity, distribution of stresses, ice thickness, area coverage and ridging. Some of the conditions leading to arch formation at the constricted exit of the channel are explored.

IFN-α Enhances Poly-IC Responses in Human Keratinocytes by Inducing Expression of Cytosolic Innate RNA Receptors: Relevance for Psoriasis

Toll-Like Receptor Signaling in Liver Diseases

Enhancing the efficacy of innate immune agonists: could nanolipoprotein particles hold the key?

Toll-like receptors(TLRs)are pattern-recognition receptors to recognize pathogen-associated molecular pattern. They play central roles in initiating innate immunity and regulating adaptive immune response. At present, it has been found that distribution and expression of functions of TLRs in hosts have intimate relations with recognizing pathogenic bacteria (such as uropathogenic Escherichia coli ), development, therapy and prognosis of urinary tract infections. TLR4 expression levels are lower in the patients with asymptomafic bacteriuria, and TLR4 mutation rates are higher in the patients with urinary tract infections. Key words: Toll-like receptors; Urinary tract infections; Escherichia coli; Immune responses

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder marked by autoantibody-mediated dysfunction at the neuromuscular junction, resulting in fluctuating muscle weakness. The pathogenesis of MG involves a complex interplay between genetic predisposition, environmental factors, and immune system dysregulation. Among these, the innate immune system, particularly Toll-like receptors (TLRs), has emerged as a critical player in disease progression by influencing both innate and adaptive immunity. TLRs are a family of pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering immune responses. Dysregulation of TLRs expression and signaling in MG has been implicated in chronic inflammation, breakdown of immune tolerance, and activation of autoreactive T and B cells. Overexpression of specific TLRs, such as TLR4 and TLR9, has been reported in MG patients, particularly in thymic tissues and peripheral immune cells, correlating with increased pro-inflammatory cytokine production and autoantibody generation. These aberrant responses contribute to the autoimmune cascade that underlies MG. Emerging evidence highlights the therapeutic potential of targeting TLRs pathways in MG. Strategies include using TLRs antagonists, modulating downstream signaling pathways, and leveraging epigenetic regulators to normalize TLRs activity. This review examines the role of TLRs in MG by exploring their expression profiles, their involvement in inflammatory signaling pathways, their impact on the adaptive immune system, and their potential as therapeutic targets. A better understanding of the role of TLRs in MG pathogenesis could open new avenues for modulating immune responses and precision therapies targeting the innate immune system.

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

The immune response to microbial pathogens relies on both innate and adaptive components.1 The innate or immediate response is mediated in large measure by leukocytes of the blood, such as neutrophils (PMNs) and macrophages, cells that phagocytose and kill the pathogens and that concurrently coordinate additional host responses by synthesis of a wide range of inflammatory mediators and cytokines.2 A primary challenge to the innate immune system is the ability to discriminate among a large number of potential pathogens from self, with the use of a restricted number of receptors. This discrimination is achieved by the evolution of a variety of receptors that recognize conserved motifs on pathogens called pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs), perhaps the best-characterized class of pattern-recognition receptors (PRRs)3,4 in mammalian species, play an important role in the recognition of components of pathogens and activation of innate immunity, which then leads to development of adaptive immune responses.5 In the eye, as in other parts of the body, the early response against invading pathogens is provided by innate immunity. It is now well established that the recognition of pathogens by the innate defense system is mediated through germ line–encoded PRRs,6,7 most notably, TLRs.4,8,9 A growing number of studies have shown that TLRs are expressed by a variety of tissues and cells of the eye and play an important role in ocular protection and defense against microbial infection.10–20 The TLR family of receptors links the extracellular compartment where contact and recognition of PAMPs occur and the intra-cellular compartment, where signaling cascades leading to cellular responses are initiated. Their extracellular domain contains leucine-rich repeats (LRRs), whereas the cytoplasmic domain shows a striking homology with that of the interleukin-1 receptor (IL-1R) and is referred to as the Toll/IL-1R (TIR) domain. The Toll/IL-1Rs play a critical role in host defense and inflammation.21 Ten TLRs have been identified in humans, whereas 13 can be found in the mouse genome.22 Individual TLRs recognize distinct microbial components or PAMPs.4 Recognition of PAMPs by TLRs induces the production of signals responsible for the activation of genes that are essential for an effective host defense, especially proinflammatory cytokine genes.8,23 One of the first mammalian receptors identified was TLR4.24,25 Figure 1 shows TLRs, their known ligands (or PAMPs), downstream signaling pathways, and their role in mediating innate responses in cells. TLR4 is the extensively studied PRR and has been shown to be capable of sensing lipopolysaccharide (LPS) and initiating responses.26 TLR2 has been shown to recognize a broad range of microbial components including bacterial and mycoplasma lipoproteins and yeast carbohydrates.27 TLR3 is necessary for the response to double-stranded RNA (dsRNA),28 TLR5 for the response to bacterial flagellin,29 TLR7 and -8 for the response to single-stranded RNA (ssRNA),30,31 and TLR9 for the response to the unmethylated CpG motifs found in both bacterial and viral DNA.32,33 There are no specific ligands identified for TLR1 and -6; however, they are known to form heterodimers with TLR2, dictating the specificity of TLR2 ligand recognition.34 Little is known about TLR10.35 Figure 1 TLR signaling and the role of epithelium in corneal innate defense. When cells are exposed to pathogens, TLRs such as TLR2, -4, and -5 at the cell surface recognize PAMPs such as lipoproteins, LPS, and flagellin, respectively. In contrast, nucleic acids ...

Studies that bridge innate immunity and various diseases are making rapid advances. Macrophages and dendritic cells play a leading role in innate immunity, using pattern recognition receptors (PRRs) to sense both pathogen invasion and danger signals. Among these PRRs, the Toll-like receptors (TLRs) play a central role in the immune response by recognizing not only pathogen-associated molecular patterns from bacteria and viruses but also damage-associated molecular patterns from dying or injured cells. These TLR family molecules facilitate not only the elimination of pathogens but also the development of various disorders, including arteriosclerosis, cancer, and metabolic syndrome. TLRs activate signaling pathways that result in the production of cytokines, chemokines, and various inducible molecules associated with the immune response. Although most components of the innate immune signaling pathways, such as the TLR family and its downstream signaling, have been identified, the physiological roles of many TLR signal-inducible proteins remain unclear. Recent studies have shown that some TLR-inducible proteins are critical in the immune response and the development of various disorders. In this review, we focus on the TLR signaling pathways and the roles of some TLR-inducible proteins.

EDITORIAL article Front. Immunol., 16 September 2015Sec. Cancer Immunity and Immunotherapy Volume 6 - 2015 | https://doi.org/10.3389/fimmu.2015.00481

Toll like receptors(TLRs) , a pattern conservative receptor superfamily are found on mammalian cell surface over the last decade. TLRs recognize distinct pathogen - associated molecular patterns, which can lead not only to the responses of the innate immunity but also to the development of the antigenspecific adaptive immunity. The expression of TLRs have changed in some carcinomas, besides, microbial composition and drugs mediate the tumor immunotherapy by the way of TLRs signal transduction. Consequently , deep studies on TLRs will provide new approaches for tumor immunotherapy. Key words: Immunity, natural; Antineoplastic protocols; Receptors, cell surface; Immunotherapy

Monocytes have emerged as critical driving force of acute inflammation. Here, we show that inhibition of Toll-like receptor 2(TLR2) dimerization by a TLR2 transmembrane peptide (TLR2-p) ameliorated DSS-induced colitis by interfering specifically with the activation of Ly6C(+) monocytes without affecting their recruitment to the colon. We report that TLR2-p directly interacts with TLR2 within the membrane, leading to inhibition of TLR2-TLR6/1 assembly induced by natural ligands. This was associated with decreased levels of extracellular signal-regulated kinases (ERK) signaling and reduced secretion of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-23, IL-12, and IL-1β. Altogether, our study provides insights into the essential role of TLR2 dimerization in the activation of pathogenic pro-inflammatory Ly6C(hi) monocytes and suggests that inhibition of this aggregation by TLR2-p might have therapeutic potential in the treatment of acute gut inflammation.

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expressions of pattern recognition receptors (PRRs) also cause diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not yet been revealed. Based on TLR4-deficient (TLR4-/-) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type 2 dendritic cells (CD8α- CD11b+ cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of follicular helper T (Tfh) cells promotes the proliferation of germinal center (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4-deficient (TLR4-/-) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG compared to that occurred in wild-type (WT) mice. As a consequence, TLR4-/- mice exhibited higher mortality than that of WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α+ CD11b-), a subset of cDCs known to induce CD4+ T-cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

Emerging viral infections are considered a global threat, and they have gained more importance after the coronavirus outbreak in 2019, which affected the whole world. The innate immune system recognizes invading pathogens via pattern recognition receptors (PRRs) expressed on different immune cells extracellularly and intracellularly. Out of several PRRs, Toll-like receptors (TLRs) are one of the critical PRRs recognizing diverse pathogen-associated molecular patterns (PAMPs) varying from viruses, bacteria, and fungi. Viral pathogens possess specific molecular signatures such as dsRNA and high CpG content that differentiate them from mammalian cells. TLRs play their role in innate immunity against pathogenic viruses by producing antiviral cytokines and chemokines. Most emerging viral pathogens are RNA viruses including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These viruses are recognized by TLR 2, TLR 3, TLR 4, TLR7, and TLR8 with the coordination of other PRR members resulting in the activation of costimulatory molecules that initiate immune response. This chapter provides insights into the TLRs’ role in developing and regulating the immune response against emerging viral pathogens. It exploits their roles in innate immunity to develop treatment strategies against deadly emerging viral pathogens.

The innate immune system provides a first line of defense against invading pathogens, in which the pattern recognition receptors (PRR) recognize pathogen-associated molecular patterns (PAMP) and initiate the downstream signaling pathways to eliminate the encountered pathogens. There are two main classes of such signaling pathways: NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. The microbial pathogens under selective pressure have evolved numerous mechanisms to avoid and/or manipulate the NLR and TLR signal transduction for survival and replication. To evade the NLR signaling pathway, pathogens interfere and/or inhibit inflammasome activation in innate immune cells by producing virulence factors or reducing PAMPs expression. The mechanisms for pathogens to evade TLR signaling pathway include: inhibition of mitogen activated protein kinases (MAPKs) cascade reaction, inhibition of NF-КB activation, and interference of down-stream signal transduction by producing Toll/interleukin-1 receptor (TIR)-containing proteins which bind directly with TLRs or adaptor proteins in the signaling pathway.