Effects Of Toll-like Receptors Research Articles

Five-hub genes identify potential mechanisms for the progression of asthma to lung cancer.

Previous studies have shown that asthma is a risk factor for lung cancer, while the mechanisms involved remain unclear. We attempted to further explore the association between asthma and non-small cell lung cancer (NSCLC) via bioinformatics analysis. We obtained GSE143303 and GSE18842 from the GEO database. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) groups were downloaded from the TCGA database. Based on the results of differentially expressed genes (DEGs) between asthma and NSCLC, we determined common DEGs by constructing a Venn diagram. Enrichment analysis was used to explore the common pathways of asthma and NSCLC. A protein-protein interaction (PPI) network was constructed to screen hub genes. KM survival analysis was performed to screen prognostic genes in the LUAD and LUSC groups. A Cox model was constructed based on hub genes and validated internally and externally. Tumor Immune Estimation Resource (TIMER) was used to evaluate the association of prognostic gene models with the tumor microenvironment (TME) and immune cell infiltration. Nomogram model was constructed by combining prognostic genes and clinical features. 114 common DEGs were obtained based on asthma and NSCLC data, and enrichment analysis showed that significant enrichment pathways mainly focused on inflammatory pathways. Screening of 5 hub genes as a key prognostic gene model for asthma progression to LUAD, and internal and external validation led to consistent conclusions. In addition, the risk score of the 5 hub genes could be used as a tool to assess the TME and immune cell infiltration. The nomogram model constructed by combining the 5 hub genes with clinical features was accurate for LUAD. Five-hub genes enrich our understanding of the potential mechanisms by which asthma contributes to the increased risk of lung cancer.

Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases.

There is growing evidence that the pathogenesis of retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) have a significant chronic inflammatory component. A vital part of the inflammatory cascade is through the activation of pattern recognition receptors (PRR) such as toll-like receptors (TLR). Here, we reviewed the past and current literature to ascertain the cumulative knowledge regarding the effect of TLRs on the development and progression of retinal diseases. There is burgeoning research demonstrating the relationship between TLRs and risk of developing retinal diseases, utilising a range of relevant disease models and a few large clinical investigations. The literature confirms that TLRs are involved in the development and progression of retinal diseases such as DR, AMD, and ischaemic retinopathy. Genetic polymorphisms in TLRs appear to contribute to the risk of developing AMD and DR. However, there are some inconsistencies in the published reports which require further elucidation. The evidence regarding TLR associations in retinal dystrophies including retinitis pigmentosa is limited. Based on the current evidence relating to the role of TLRs, combining anti-VEGF therapies with TLR inhibition may provide a longer-lasting treatment in some retinal vascular diseases.

The Association Between Gut Microbiota, Toll-Like Receptors, and Colorectal Cancer

The large number of microbes found in the gut are involved in various critical biological processes in the human body and have dynamic and complex interactions with the immune system. Disruptions in the host's gut microbiota and the metabolites produced during fermentation promote the development of intestinal inflammation and colorectal cancer (CRC). Toll-like receptors (TLRs) recognize specific microbial-associated molecular patterns specific to microorganisms whose signaling is involved in maintaining intestinal homeostasis or, under certain conditions, mediating dysbiosis-associated intestinal inflammation. The signaling pathways of TLRs are described first, followed by a discussion of the interrelationship between gut microbes and TLRs, including the activation of TLRs by gut microbes and the effect of TLRs on the distribution of gut microbiota, particularly the role of microbes in colorectal carcinogenesis via TLRs. Finally, we discuss the potential roles of various TLRs in colorectal cancer.

Retinal Pigment Epithelium Expressed Toll-like Receptors and Their Potential Role in Age-Related Macular Degeneration.

(1) Background: Inflammation is a major pathomechanism in the development and progression of age-related macular degeneration (AMD). The retinal pigment epithelium (RPE) may contribute to retinal inflammation via activation of its Toll-like receptors (TLR). TLR are pattern recognition receptors that detect the pathogen- or danger-associated molecular pattern. The involvement of TLR activation in AMD is so far not understood. (2) Methods: We performed a systematic literature research, consulting the National Library of Medicine (PubMed). (3) Results: We identified 106 studies, of which 54 were included in this review. Based on these studies, the current status of TLR in AMD, the effects of TLR in RPE activation and of the interaction of TLR activated RPE with monocytic cells are given, and the potential of TLR activation in RPE as part of the AMD development is discussed. (4) Conclusion: The activation of TLR2, -3, and -4 induces a profound pro-inflammatory response in the RPE that may contribute to (long-term) inflammation by induction of pro-inflammatory cytokines, reducing RPE function and causing RPE cell degeneration, thereby potentially constantly providing new TLR ligands, which could perpetuate and, in the long run, exacerbate the inflammatory response, which may contribute to AMD development. Furthermore, the combined activation of RPE and microglia may exacerbate neurotoxic effects.

Toll-Like Receptor Characterization Correlates with Asthma and Is Predictive of Diagnosis.

Toll-like receptors (TLRs) play crucial roles in the recognition of invading pathogens and the immune system. However, the effect of TLRs in asthma is still not fully known. This study was performed to better understand the role of TLR signatures in asthma. Blood samples from case-control studies (study 1: 348 asthmas and 39 normal controls and validation study 2: 411 asthmas and 87 normal controls) were enrolled. The single-sample gene set enrichment analysis method was performed to quantify the abundance of 21 TLR signatures. Gene ontology analysis and pathway function analysis were conducted for functional analysis, and a protein-protein interaction network was constructed. The area under the curve (AUC) value was used to assess the diagnostic capacity. In this study, TLR2/TLR3/TLR4 pathway, MyD88-dependent/independent TLR pathway, positive regulation of TLR4 pathway, and TLR binding signatures were significantly higher in asthma. Functional analysis showed that biological processes and pathways were still involved in TLR cascades and TLR signaling pathway. Eleven hub TLR-related genes were identified, and further validation demonstrated that the combination of TLR-related genes was a good diagnostic biomarker for asthma (AUC = 0.8). Our study provided more insight into the underlying immune mechanism of how TLR signatures affected asthma. The use of the easy-to-apply TLR-related genes might represent a promising blood-based biomarker for early detection of asthma.

Increased expression of interleukin 36 in chronic rhinosinusitis and its contribution to chemokine secretion and increased epithelial permeability

BackgroundIL-36 family, a recently reported member of the IL-1 cytokine family, plays an essential role in nonspecific innate immune response to infection. This study aims at investigating the expression of IL-36 family members (α, β, and γ) in normal and inflammatory sinus mucosa of patients with chronic rhinosinusitis (CRS), their effects on chemokine secretion and on the barrier function of epithelial and endothelial cells, and the effect of Toll-like receptors on the expression of IL-36 in epithelial cells. Material and methodsThe expression of IL-36 family in normal and inflammatory sinus mucosa, the production of chemokines or the expression levels of IL-36 family in epithelial cells treated with IL-36 family members or stimulated with TLR3, TLR4, TLR5, or TLR7/8 agonists were measured with real time PCR, ELISA, immunohistochemistry, or Western blot.The epithelial and endothelial permeability, and transendothelial leukocyte migration were investigated using cultured epithelial and endothelial cells. ResultsIL-36α, IL-36β, and IL-36γ were localized in epithelial cells of sinonasal mucosa. Their levels increased in inflammatory mucosa of CRS patients and are up-regulated by TLR3, TLR4, or TLR5 agonists. IL-36α, or IL-36γ induced CXCL1, CXCL2, and CXCL3 production. Epithelial and endothelial permeability, transendothelial leukocyte migration were increased in cells treated with IL-36α, IL-36β, or IL-36γ. ConclusionsThese results suggest that IL-36α, IL-36β, and IL-36γ localized in superficial epithelium may act as a responder to microbial and nonmicrobial elements through TLR and subsequently produce CXC chemokines, playing an interplay between innate and adaptive immune response.

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

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

Regulation of airway inflammation and remodeling in asthmatic mice by TLR3/TRIF signal pathway.

This paper aims to investigate the effect of Toll-like receptors 3 (TLR3)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway on the airway inflammation and remodeling in asthmatic mice. C57BL/6 and TLR3-/- mice were randomly divided into three groups (10 mice per group), including Control group (mice inhaled phosphate buffer saline (PBS)), Asthma group (mice inhaled ovalbumin (OVA)) and polyriboinosinic-ribocytidylic acid (poly (I: C)) group (asthmatic mice were injected intraperitoneally with TLR3 agonist poly (I: C)). Hematoxylin-eosin (HE) staining, Wright-Giemsa staining, Enzyme-linked immunosorbent assay (ELISA), Immunohistochemistry, Hydroxyproline assay, quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to assess for the indices of airway inflammation and remodeling. In terms of WT mice, all asthma groups with or without the addition of poly (I: C) showed exaggerated inflammation and remodeling in the airways as compared to Control group, which were more seriously in poly (I: C) group than Asthma group. Furthermore, we observed the significant inhibition of airway inflammation and remodeling in the TLR3-/- mice in both Asthma no matter with or without addition of poly (I: C) than the WT mice. TLR3 knockout could obviously relieve the airway inflammation and remodeling in asthma through inhibiting TLR3/TRIF signaling pathway.

Toll-Like Receptor 3 and Interferon β mRNA Expressions Were Increased in Peripheral Blood of Ischemic Stroke Patients with Good Outcome

Innate immunity plays an important role in brain ischemic injury, but there are only few studies on the effects of toll-like receptors (TLRs) on cerebral infarction patients up to now. We aimed to evaluate the TLR mRNA expression of patients with different outcomes. Eighty-six cases suffering from cerebral infarction within 14 days were assigned into the good outcome group (n = 47) and the bad outcome group (n = 39) depending on the modified Rankin Scale scores (mRS ≤2 at 90 days following stroke onset was good outcome). We measured the mRNA expression of TLRs in peripheral blood mononuclear cells of patients at 24 hours, 3 days, 4 days, 7 days, and 14 days from onset. The National Institutes of Health Stroke Scale score and infarction volume were assessed on admission and at 7-14 days, respectively. Only TLR3 mRNA expression of the good outcome group was higher than that of the bad outcome group at acute and subacute phases. TLR7 expressions of the good outcome group increased within 3 days following stroke onset. Moreover, the two groups had no significant differences in terms of mRNA expressions of TLR2, TLR4, TLR8, and TLR9. The expression of interferon β of the good outcome group was higher than that of the bad outcome group, and it had a positive correlation with the expressions of TLR3 and interferon regulatory factor 3. TLR3 and interferon β mRNA expressions were increased in the peripheral blood of ischemic stroke patients with good outcome, which may imply their neuroprotection.

Monocyte Toll-Like Receptor Expression in Patients With Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Inflammation has been suggested to play a vital role in the pathogenesis. Previous studies have investigated expression of inflammatory markers in AF. Several studies have focused on the effects of toll-like receptors (TLRs) on heart in terms of capability of modulating inflammation. In this study, we aimed to investigate whether peripheral monocyte TLR expression was associated with the AF presence, and recurrence of AF after cryoablation, as a reflection of inflammatory status. Patients with AF who were scheduled for cryoballoon-based ablation for AF and age- and gender-matched subjects in sinus rhythm were included. Peripheral monocyte TLR-2 and TLR-4 expressions were evaluated by flow cytometric analysis in peripheral venous blood samples obtained during evaluation in outpatient clinics: 172 patients (56.5 ± 6.6 years, 52.3% men) were included in the study. Peripheral monocyte TLR-2 and TLR-4 expression levels were significantly higher in patients with AF (p <0.05). Among patients with AF, 12 patients (14.0%) developed AF recurrence at a follow- up of 17 months. Multivariate Cox regression analysis showed that left atrial volume index (hazard ratio 2.040, 95% CI 1.197 to 3.477, p = 0.009) and monocyte TLR-4 expression (hazard ratio 1.226, 95% CI 1.042 to 1.443, p = 0.014) were independent predictors of AF recurrence after blanking period following second-generation cryoballoon-based pulmonary vein isolation for paroxysmal AF. In conclusion, our study highlights the role of TLR-mediated inflammation in the pathogenesis of AF. This link may also constitute a therapeutic target in patients with AF.

Influence of TLR2- and TLR4-activated Mesenchymal Stem Cells on Migration of Cord Blood CD34+ Cells

This study was aimed to investigate the possible effect of Toll-like receptors 2 (TLR2) and Toll-like receptors 4 (TLR4) on the migration function of umbilical cord blood (UCB) CD34+ hematopoietic stem/progenitor cells induced by bone marrow-derived mesenchymal stem cells (MSCs) and to explore the underlying mechanism. The expression of TLR2 and TLR4 on MSC was detected with flow cytometry. After the MSC were pretreated with TLR2 agonist (PAM3CSK4) and/or TLR4 agonist (LPS), the supernatants were collected. The effect of the supernatants on the migration of CD34+ cells was evaluated with chemotaxis assays. Alterations of chemokine (SDF-1) secreted by MSC in the supernatants were assayed by ELISA. The expression levels of TLR2 and TLR4 were (31.5±4.6)% and (85.6±6.7)% respectively. Compared with the blank group, the migration ability of CD34+ cells increased significantly in control, LPS and/or PAM3CSK4 groups (P<0.01). Further study found that LPS and/or PAM3CSK4 enhanced the chemotactic ability of CD34+ cells (P<0.05), but the concentration of SDF-1 was not changed significantly in all of LPS and/or PAM3CSK4 groups (P>0.05) in comparison with the control group. TLR2 and TLR4 signalings may indirectly increase the migration of CD34+ hematopoietic stem/progenitor cells by modulating BM-MSC functions, which may not significantly correlate with the production of chemokine SDF-1 by MSCs.

Effects of Toll-like Receptors 3 and 4 Induced by Titanium Dioxide Nanoparticles in DNA Damage-Detecting Sensor Cells

Live cell-based sensor reporter systems (so-called sensor cells) were employed to detect host defense systems, including DNA damage response, stimulated by nanoparticles (NPs). Our previous work established the use of DNA damage-detecting sensor cells containing the B-cell translocation gene 2(BTG2) promoter-reporter plasmid and showed that Toll-like receptors (TLRs) are involved in the cellular response and uptake of TiO2 NPs. These results suggested that TLRs could be involved in many cellular responses. However, the effect of TLRs on DNA damage induced by TiO2 NPs is unknown. Here we investigated the role of TLR 3 and 4 in DNA damage induced by PEG- 2 NPs reduces DNA damage response compared to unmodified TiO2 NPs. The overexpression of TLR3 reduces DNA damage mediated by both TiO2 and PEG-TiO2 NPs. In contrast, overexpression of TLR4 increases the DNA damage response induced by TiO2 NPs. The results indicate that co-transfection of TRL4 expression vector affects the sensitivity of DNA damage response, but does not affect the detection limit of the DNA damage response. These finding will aid in understanding the molecular interaction mechanisms between NPs and cells.

The innate immune system in Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid β (Aβ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

Porphyromonas gingivalis and its lipopolysaccharide differentially regulate the expression of cathepsin B in endothelial cells

Porphyromonas gingivalis infection and cathepsins protease upregulation are independently implicated in atherosclerosis worsening. In this study, we evaluated the effects of P. gingivalis infection and P. gingivalis -purified lipopolysaccharide (Pg-LPS) stimulation on the expression of cathepsin B (CATB) in endothelial cells (ECs). Analysis of the enzymatic activity and expression of CATB were investigated at the messenger RNA, protein and protein-phosphorylation levels. Effects of Toll-like receptors 2 and 4 blocking on CATB activity were also analysed. Our results showed that P. gingivalis and Pg-LPS significantly increased the activity of CATB but with different kinetics. The peak of CATB activity was observed 3 h after P. gingivalis infection but it appeared 48 h after Pg-LPS stimulation. The increase of CATB activity was related to its rapid tyrosine-dephosphorylation during P. gingivalis infection, whereas the levels of CATB messenger RNAs and proteins did not vary after P. gingivalis infection or Pg-LPS stimulation. Inhibition of Toll-like-receptors 2 and 4 differentially decreased P. gingivalis and Pg-LPS CATB activations. These results showed for the first time that P. gingivalis infection rapidly affects ECs and modulates CATB activity, whereas Pg-LPS effects appear to be delayed. This study suggests that direct infection of ECs by P. gingivalis may worsen atherosclerotic plaque formation via activation of the CATB pathway.

Toll-Like Receptors (TLRs): The Role in Tumor Progression

Toll-like receptors (TLRs) are major components of the innate immune system that recognize the conserved molecular structures of pathogens (pathogen-associated molecular patterns; PAMPs). TLRs are found in many different cell types, ranging from epithelial to immunocompetent cells. TLR binding triggers the expression of several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators. This results in the activation of both the innate immune response (elevated expression of antiapoptotic proteins, proinflammatory cytokines, and antibacterial proteins), as well as the adaptive immune response (maturation of the dendritic cells, antigen presentation, etc.). In consequence of their ability to enhance the specific and nonspecific immune reactions of an organism, TLR agonists are widely used in the therapy of infectious diseases and, as adjuvants, in the therapy of malignant neoplasia. However, to date, TLRs have had the opposite effects on tumor progression. On the one hand, TLR ligands can suppress tumor growth. On the other hand, TLR agonists can promote the survival of malignant cells and increase their resistance to chemotherapy. The purpose of this review is to summarize the available data on the effects of TLRs and their agonists on tumor progression, as well as the mechanisms underlying the differences in the effects of TLRs on tumor growth.

Effect of Toll-like receptors in immunity of gastrointestinal tract

人体胃肠道定居着一群非致病性共生菌,同时又频繁接触各种致病性病原体.为维持胃肠道内环境稳定,宿主必须Ⅸ分致病和非致病性微牛物,同时能有效启动合适的免疫和炎症应答.哺乳动物Toll样受体是模式识别受体家族成员,在启动对病原体进行固有免疫和获得性免疫应答中起重要作用.研究表明胃肠道上皮细胞几乎表达迄今为止发现的所有Toll样受体亚型.胃肠道Toll样受体表达和激活是相互协同调节的.该文概述了胃肠道上皮细胞Toll样受体在共生菌免疫耐受、胃肠道感染防御及胃肠道炎症中的作用。

Toll like receptors in autoimmune inflammatory demyelination: relevance to Multiple Sclerosis

Multiple Sclerosis is a demyelinating disease of the central nervous system. We aim to find mechanisms by which toll like receptors (TLRs) exacerbate or suppress CNS inflammatory demyelination. Both effects have been observed in an animal model of MS ‐ TLRs 2 and 9 in exacerbating disease, TLR4 in delaying onset and TLR3 in reducing severity. We studied the response of human monocyte derived dendritic cells (MDDCs) to TLR stimuli in terms of maturation and cytokine and chemokine production. The inflammatory chemokine MCP‐1 was unregulated by TLR stimuli poly(I:C) (TLR3) and lipopolysaccharide (LPS) (TLR4). The inflammatory cytokines IL‐6 and TNF‐α were unregulated by these two stimuli and also by Pam3CSK4 (TLR1/2) and HKLM (TLR2). The effects of TLRs on MDDCs in MS patients are in progress. We also determined which cytokines and chemokines are induced by TLR stimuli in murine splenocytes. MCP‐1 was unregulated by TLR stimuli ‐ Pam3CSK, HKLM, LPS, Flagellin (TLR5), follistatin‐like 1 (TLR6) and ssRNA40 (TLR7). The anti‐inflammatory cytokine IL‐10 was unregulated by the same stimuli and also by poly(I:C) and CpG ODN1826 (TLR9). TLR9 also induced increased production of IL12p70. All TLR stimuli also induced increased T cell proliferation. The production of cytokines in response to TLR stimuli may regulate autoimmune diseases and there is potential to aid immunotherapy by targeting these TLRs and the cytokines produced.

The Effect of Toll-Like Receptors and Toll-Like Receptor Genetics in Human Disease

Toll-like receptors (TLRs) enable innate immune recognition of endogenous and exogenous prototypic ligands. They also orchestrate innate and adaptive immune response to infection, inflammation, and tissue injury. Given their significance in the immune response, it is not surprising that genetic variations of TLRs can affect their function and by extension affect the response of the organism to environmental stimuli. The genetics of TLRs provides important insights in gene-environment interactions in health and disease, and it may enable scientists to assess patients' susceptibility to diseases or predict their response to treatments.

What's in a Vaccine?

After vaccination, the efficiency with which protective antibodies are produced often depends on the presence of an adjuvant, a substance that promotes activation of antibody-producing B cells. It has been anticipated that Toll-like receptors (TLRs) might be major players in mediating the effects of adjuvants. However, Gavin et al. now find that the known TLR pathways do not modulate B cell responses, and so adjuvants containing TLR ligands must depend on other properties. Such a revision to thinking about the effects of TLR on B cell responses will likely refocus current thinking about vaccine development. A. L. Gavin, K. Hoebe, B. Duong, T. Ota, C. Martin, B. Beutler, D. Nemazee, Adjuvant-enhanced antibody responses in the absence of Toll-like receptor signaling. Science 314 , 1936-1938 (2006). [Abstract] [Full Text]