The Role of Toll-like Receptors (TLRs) Mediated Inflammation in Pancreatic Cancer Pathophysiology.
Ontology highlight
ABSTRACT:
SUBMITTER: Orlacchio A
PROVIDER: S-EPMC8657588 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundToll-like receptors (TLRs) are important components of the innate and adaptive immune systems, and abnormal TLR expression has been linked to a variety of cancers. However, there was a lack of clarity on the association of TLR stimulation with the carcinogenesis of cancer. The study's goal was to analyse the clinical importance of TLRs expression at the mRNA level in pan-cancer datasets, as well as the link between TLR expression and carcinogenesis, progression, and clinical prognosis.MethodsThe expression profile of TLRs derived from UCSC pan-cancer data was analysed in multiple dimensions, including clinical analysis, immunological subtype analysis, tumour microenvironment (TME) analysis, tumour stem cell correlation analysis, and drug sensitivity analysis. Additionally, we analyse protein-protein interactions, functional enrichment, and chromatin accessibility, as well as TLR expression in single-cell sequencing data.ResultsOur multi-omics analysis results imply that TLRs may operate as a biological marker for carcinogenesis and progression, a potential target for anti-tumour therapy, and a prognostic biomarker, laying the theoretical groundwork for future translational medicine research.ConclusionTLRs are involved in the formation of malignancies and can be explored in further detail as potential prognostic indicators. Key MessagesToll-like receptors (TLRs) are key factors in the process of the innate and adaptive immune response, and their aberrant expression of TLRs have been widely reported in various cancer. However, the association between TLRs stimulation and tumorigenesis of cancer has not been well clarified.In this study, in the pan-cancer data, integrated TLR family gene expression analysis, clinical correlation analysis, immune subtype correlation analysis, tumour microenvironment correlation analysis, tumour stem cell correlation analysis, and drug sensitivity correlation analysis were performed.TLRs play an important role in the development of tumours and can be studied in depth as potential prognostic markers.
| S-EPMC9272932 | biostudies-literature
Project description:Toll-like receptors (TLRs) are the important mediators of inflammatory pathways in the gut which play a major role in mediating the immune responses towards a wide variety of pathogen-derived ligands and link adaptive immunity with the innate immunity. Numerous studies in different populations across the continents have reported on the significant roles of TLR gene polymorphisms in modulating the risk of colorectal cancer (CRC). CRC is one of the major malignancies affecting the worldwide population and is currently ranking the third most common cancer in the world. In this review, we have attempted to discuss the structure, functions, and signaling of TLRs in comprehensive detail together with the role played by various TLR gene SNPs in CRC susceptibility.
| S-EPMC8452412 | biostudies-literature
Project description:ObjectivesToll-like receptors (TLRs) play a pivotal role in the immune system and carcinogenesis. There is no research on TLR expression and association with survival among preoperatively treated pancreatic cancer patients. We studied the expression intensity and prognostic value of TLRs in pancreatic cancer patients treated with neoadjuvant therapy (NAT) and compared the results to patients undergoing upfront surgery (US).MethodBetween 2000 and 2015, 71 borderline resectable patients were treated with NAT and surgery and 145 resectable patients underwent upfront surgery at Helsinki University Hospital, Finland. We immunostained TLRs 1-5, 7, and 9 on sections of tissue-microarray. We classified TLR expression as 0 (negative), 1 (mild), 2 (moderate), or 3 (strong) and divided into high (2-3) and low (0-1) expression for statistical purposes.ResultsAmong TLRs 1, 3, and 9 (TLR1 81% vs 70%, p = 0.008; TLR3 92% vs 68%, p = 0.001; TLR9 cytoplasmic 83% vs 42%, p<0.001; TLR9 membranous 53% vs 25%, p = 0.002) NAT patients exhibited a higher immunopositivity score more frequently than patients undergoing upfront surgery. Among NAT patients, a high expression of TLR1 [Hazards ratio (HR) 0.48, p<0.05] associated with a longer postoperative survival, whereas among US patients, high expression of TLR5 (HR 0.64, p<0.05), TLR7 (HR 0.59, p<0.01, and both TLR7 and TLR9 (HR 0.5, p<0.01) predicted a favorable postoperative outcome in separate analysis adjusted for background variables.ConclusionsWe found higher immunopositive intensities among TLRs 1, 3, and 9 in NAT patients. A high TLR1 expression associated with a longer survival among NAT patients, however, among US patients, high expression intensity of TLR5 and TLR7 predicted a favorable postoperative outcome in the adjusted analysis.
| S-EPMC9089880 | biostudies-literature
Project description:Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) expressed in various immune cell types and perform multiple purposes and duties involved in the induction of innate and adaptive immunity. Their capability to propagate immunity makes them attractive targets for the expansion of numerous immunotherapeutic approaches targeting cancer. These immunotherapeutic strategies include using TLR ligands/agonists as monotherapy or combined therapeutic strategies. Several TLR agonists have demonstrated significant efficacy in advanced clinical trials. In recent years, multiple reports established the applicability of TLR agonists as adjuvants to chemotherapeutic drugs, radiation, and immunotherapies, including cancer vaccines. Cancer vaccines are a relatively novel approach in the field of cancer immunotherapy and are currently under extensive evaluation for treating different cancers. In the present review, we tried to deliver an inclusive discussion of the significant TLR agonists and discussed their application and challenges to their incorporation into cancer immunotherapy approaches, particularly highlighting the usage of TLR agonists as functional adjuvants to cancer vaccines. Finally, we present the translational potential of rWTC-MBTA vaccination [irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists Mannan-BAM, TLR ligands, and anti-CD40 agonisticAntibody], an autologous cancer vaccine leveraging membrane-bound Mannan-BAM, and the immune-inducing prowess of TLR agonists as a probable immunotherapy in multiple cancer types.
| S-EPMC10626551 | biostudies-literature
Project description:Members of the family Suidae have diverged over extended evolutionary periods in diverse environments, suggesting that adaptation in response to endemic infectious agents may have occurred. Toll-like receptors (TLRs) comprise a multigene family that acts as the first line of defense against infectious microbes at the host-environment interface. We hypothesized that across the Suidae, positive selection mediated by infectious agents has contributed to the evolution of TLR diversity. Thus, we analyzed Sus scrofa, Sus barbatus, Sus verrucosus, Sus celebensis, Sus scebifrons, Babyrousa babyrussa, Potamochoerus larvatus, Potamochoerus porcus and Phacochoerus africanus genomes. Specifically, analyses were performed to identify evidence of positive selection using Maximum likelihood (ML) methods within a phylogenetic framework for bacterial and viral sensing Suidae TLR extracellular domains. Our analyses did not reveal evidence of positive selection for TLR3 and TLR7, suggesting strong functional conservation among these two genes for members of the Suidae. Positive selection was inferred for Suidae TLR1, TLR2, TLR6 and TLR8 evolution. ML methods identified amino acid sites of the bacterial sensing TLR1, TLR2, TLR6 and the viral sensing TLR8 to be under persistent positive selection. Some of these sites are in close proximity to functionally relevant sites, further strengthening the case for pathogen mediated selection for these sites. The branch leading to the genus Sus demonstrated evidence of episodic positive selection for TLR1, indicating selection mediated by infectious agents encountered within the specific geographic origin of the Sus. These results indicate that species of the Suidae have positively selected residues within functional domains of TLRs reflective of prior infections. Thus, TLR genes represent candidates for experimental validation to determine their functional role in antibacterial and antiviral activity within members of the Suidae.
| S-EPMC4404360 | biostudies-literature
Project description:Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer’s, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.
| S-EPMC10452856 | biostudies-literature
Project description:Interferon regulatory factors (IRFs) are crucial for transcription during innate immune responses. We have previously shown that the tyrosine kinase c-Src enhances IRF-3-dependent transcription in response to viral double-stranded RNA. In this study, we show that c-Src has distinct roles in Toll-like receptor (TLR)-mediated activation of IRF-5 and IRF-3. Surprisingly, c-Src inhibition markedly enhanced IRF-5 activation after treatment with unmethylated CpG, while suppressing IRF-3 activation. Also, CpG-elicited interleukin-6 mRNA production was increased, whereas IP10 mRNA synthesis was reduced in cells deficient in c-Src. Interestingly, c-Src regulated TLR-stimulated induction of activating transcription factor 3 (ATF3), a transcriptional repressor. Depletion of ATF3 by small interfering RNA markedly enhanced interleukin-6 production after CpG treatment, whereas IP10 production was reduced. These results demonstrate functional specificity for c-Src in TLR-stimulated responses and suggest that c-Src modulation and ATF3 activity may contribute to differential regulation of IRF-3- versus IRF-5-mediated gene expression.
| S-EPMC2878043 | biostudies-literature
Project description:Allergic rhinitis represents a global health issue affecting 10% to 25% of the population worldwide. Over the years, studies have found that allergic diseases, including allergic rhinitis, are associated with immunological responses to antigens driven by a Th2-mediated immune response. Because Toll-like receptors (TLRs) are involved in both innate and adaptive immune responses to a broad variety of antigens, the association between polymorphisms of TLRs and allergic diseases has been the focus in many animal and human studies. Although the etiology of allergic rhinitis is still unknown, extensive research over the years has confirmed that the underlying causes of allergic diseases are due to many genetic and environmental factors, along with the interactions among them, which include gene-environment, gene-gene, and environment-environment interactions. Currently, there is great inconsistency among studies mainly due to differences in genetic background and unique gene-environment interactions. This paper reviews studies focusing on the association between TLR polymorphisms and allergic diseases, including allergic rhinitis, which would help researchers better understand the role of TLR polymorphisms in the development of allergic rhinitis, and ultimately lead to more efficient therapeutic interventions being developed.
| S-EPMC3681168 | biostudies-literature
Project description:The pathogenesis of gastroesophageal reflux disease (GERD) is not fully understood. It involves the activation of mucosal immune-mediated and inflammatory responses. Toll-like receptors (TLR) 2 and TLR4 are pattern-recognition receptors of the innate immune system; they recognize microbial and endogenous ligands. Farnesoid X receptor (FXR) is a bile acid receptor that regulates the inflammatory response. We aimed to evaluate TLR2, TLR4 and FXR expression patterns in GERD. We re-evaluated 84 oesophageal biopsy samples according to the global severity (GS) score, including 26 cases with histologically normal oesophagus, 28 with histologically mild oesophagitis and 30 with severe oesophagitis. We used immunohistochemistry and in situ hybridization to assess the expression patterns of TLR2, TLR4 and FXR in oesophageal squamous cells. Immunohistochemistry showed that nuclear and cytoplasmic TLR2 was expressed predominantly in the basal layer of normal oesophageal epithelium. In oesophagitis, TLR2 expression increased throughout the epithelium, and the superficial expression was significantly more intensive compared to normal epithelium, p <0.01. Nuclear and cytoplasmic TLR4 was expressed throughout the thickness of squamous epithelium, with no change in oesophagitis. FXR was expressed in the nuclei of squamous cells, and the intensity of the expression increased significantly in oesophagitis (p <0.05). FXR expression correlated with basal TLR2. In situ hybridization confirmed the immunohistochemical expression patterns of TLR2 and TLR4. In GERD, TLR2, but not TLR4, expression was upregulated which indicates that innate immunity is activated according to a specific pattern in GERD. FXR expression was increased in GERD and might have a regulatory connection to TLR2.
| S-EPMC8364528 | biostudies-literature
Project description:While platelet function has traditionally been described in the context of maintaining vascular integrity, recent evidence suggests that platelets can modulate inflammation in a much more sophisticated and nuanced manner than previously thought. Some aspects of this expanded repertoire of platelet function are mediated via expression of Toll-like receptors (TLRs). TLRs are a family of pattern recognition receptors that recognize pathogen-associated and damage-associated molecular patterns. Activation of these receptors is crucial for orchestrating and sustaining the inflammatory response to both types of danger signals. The TLR family consists of 10 known receptors, and there is at least some evidence that each of these are expressed on or within human platelets. This review presents the literature on TLR-mediated platelet activation for each of these receptors, and the existing understanding of platelet-TLR immune modulation. This review also highlights unresolved methodological issues that potentially contribute to some of the discrepancies within the literature, and we also suggest several recommendations to overcome these issues. Current understanding of TLR-mediated platelet responses in influenza, sepsis, transfusion-related injury and cardiovascular disease are discussed, and key outstanding research questions are highlighted. In summary, we provide a resource-a "researcher's toolkit"-for undertaking further research in the field of platelet-TLR biology.
| S-EPMC7504402 | biostudies-literature