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1
Zhang, Zhe, Jean-Pierre Louboutin, Daniel J. Weiner, Joanna B. Goldberg, and James M. Wilson. "Human Airway Epithelial Cells Sense Pseudomonas aeruginosa Infection via Recognition of Flagellin by Toll-Like Receptor 5." Infection and Immunity 73, no. 11 (November 2005): 7151–60. http://dx.doi.org/10.1128/iai.73.11.7151-7160.2005.
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ABSTRACT Pseudomonas aeruginosa, an opportunistic respiratory pathogen that infects the majority of patients with cystic fibrosis, initiates host inflammatory responses through interaction with airway epithelial cells. The Toll-like receptors (TLRs) are a family of pathogen pattern recognition receptors that play key roles in host innate immunity. In this study we aimed to determine whether TLRs mediate the interaction between P. aeruginosa and airway epithelial cells. Individual murine TLRs (TLR1 to TLR9) and dual combinations of these TLRs that activate an NF-κB-driven luciferase reporter in response to PAO1 were screened in HEK 293 cells. TLR5, TLR2, a combination of TLR1 and TLR2, or a combination of TLR2 and TLR6 responded to PAO1. Another P. aeruginosa strain, strain PAK, activated TLR5 similarly, while the isogenic flagellin-deficient strain PAK/fliC and the flagellum-free bacterium Haemophilus influenzae failed to activate TLR5. Reverse transcription-PCR was used to probe the presence of multiple TLRs (including TLR5) in primary human airway epithelial cells (HAECs). Immunostaining with TLR5 antibodies showed that TLR5 was expressed in HAECs and on the apical surface of the human trachea epithelium. In HAECs, PAO1, PAK, and Burkholderia cepacia, but not flagellin-deficient strain PAK/fliC or a B. cepacia fliC mutant, activated the NF-κB reporter. Dominant negative TLR5 specifically blocked the response to P. aeruginosa but not to the response to lipoteichoic acid, a specific ligand of TLR2. We also determined that MyD88, IRAK, TRAF6, and Toll-interacting protein (Tollip), but not TIRAP, were involved in the TLR-mediated response to P. aeruginosa in HAECs. These findings demonstrate that the airway epithelial receptor TLR5 senses P. aeruginosa through its flagellin protein, which may have an important role in the initiation of the host inflammatory reaction to clear the invading pathogen.
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Fulkerson, Patricia C., Kaila L. Schollaert, H. Leighton Grimes, and Marc E. Rothenberg. "Toll-Like Receptor Signaling Inhibits Eosinophilopoiesis." Blood 116, no. 21 (November 19, 2010): 1558. http://dx.doi.org/10.1182/blood.v116.21.1558.1558.
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Abstract Abstract 1558 Eosinophils and their progenitors are robustly elevated in the bone marrow in response to diverse stimuli including helminth infection and allergic triggers. In contrast, bacterial infection results in diminution in the number of circulating eosinophils. Markedly reduced peripheral blood eosinophils of sudden onset but prolonged duration is generally a consequence of acute bacterial infection. Further, eosinopenia has been shown to be a sensitive marker of sepsis and correlates with severity of disease in critically ill patients. While the initial eosinopenic response is believed to be secondary to rapid migration of circulating eosinophils to the site of infection, the mechanism for prolonged eosinophil depletion with bacterial infection remains undefined. As Toll-like receptors (TLRs) have been shown to be expressed by early hematopoietic progenitors and by mature eosinophils, we initially investigated TLR expression during eosinophil differentiation. In a culture system we developed to differentiate mature eosinophils from low density bone marrow progenitors, IL-5 stimulation of progenitors resulted in induced expression of seven TLRs, including TLR1 (4-fold), TLR4 (5-fold), TLR6 (2-fold), TLR7 (6-fold), TLR8 (4-fold), TLR9 (3-fold), and TLR13 (8-fold), when compared to expression in the progenitors prior to IL-5-induced differentiation. Notably, a majority of the TLRs (TLR1, TLR4, TLR7, TLR8, TLR9, and TLR13) were induced specifically early in eosinophil differentiation after 4 days of IL-5 stimulation and prior to expression of surface markers, including Siglec-F and CCR3, associated with mature eosinophils. To study the effects of TLR signal transduction on eosinophil development, we exposed bone marrow progenitors to TLR agonists for 18 hours after 4 days of IL-5 stimulation and then subsequently induced further eosinophil differentiation with IL-5 stimulation for another 8 days. We measured effects of TLR signaling on cell number, eosinophil differentiation, cytokine production and protease activity. LPS stimulation resulted in a reduction in total cell numbers by more than 65% with immature eosinophils a predominant cell type. In addition, LPS stimulation of progenitors resulted in significantly increased cytokine and chemokine production, including IL-6 (80-fold) and CCL22 (2-fold), and protease activity (2-fold) after 4–6 days of subsequent IL-5 stimulation compared to IL-5 stimulation alone. Similarly, stimulation of eosinophil progenitors with the TLR1/TLR2 agonist PAM3CSK4 or TLR6/TLR2 agonist PAM2CSK4 for 18 hours resulted in markedly decreased total cell numbers in a dose-dependent manner after 3 days of subsequent IL-5 stimulation. Together, these data suggest that TLR signaling in progenitors results in inhibition of IL-5-stimulated eosinophil development with aberrant cytokine, chemokine and protease production. As eosinophil granules have been shown to have anti-bacterial properties and eosinophilia improves survival rate in an experimental bacterial peritonitis model, delineation of the mechanism of infection-induced eosinopenia may lead to novel adjuvant therapeutics for bacteremic critically ill patients. Disclosures: No relevant conflicts of interest to declare.
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Thwaites, Ryan S., Sarah Unterberger, Giselle Chamberlain, Karen Walker-Bone, Kevin A. Davies, and Sandra Sacre. "TLR1/2 and 5 induce elevated cytokine levels from rheumatoid arthritis monocytes independent of ACPA or RF autoantibody status." Rheumatology 59, no. 11 (June 28, 2020): 3533–39. http://dx.doi.org/10.1093/rheumatology/keaa220.
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Abstract Objective RA is an autoimmune inflammatory joint disease. Both RF and ACPA are associated with more progressive disease and higher levels of systemic inflammation. Monocyte activation of toll-like receptors (TLRs) by endogenous ligands is a potential source of increased production of systemic cytokines. RA monocytes have elevated TLRs, some of which are associated with the disease activity score using 28 joints (DAS28). The aim of this study was to measure TLR-induced cytokine production from monocytes, stratified by autoantibody status, to assess if their capacity to induce cytokines is related to autoantibody status or DAS28. Methods Peripheral blood monocytes isolated from RA patients and healthy controls were stimulated with TLR1/2, TLR2/6, TLR4, TLR5, TLR7, TLR8 and TLR9 ligands for 18 h before measuring IL-6, TNFα and IL-10. Serum was used to confirm the autoantibody status. Cytokine levels were compared with RF, ACPA and DAS28. Results RA monocytes demonstrated significantly increased IL-6 and TNFα upon TLR1/2 stimulation and IL-6 and IL-10 upon TLR5 activation. TLR7 and TLR9 activation did not induce cytokines and no significant differences were observed between RA and healthy control monocytes upon TLR2/6, TLR4 or TLR8 activation. When stratified by ACPA or RF status there were no correlations between autoantibody status and elevated cytokine levels. However, TLR1/2-induced IL-6 did correlate with DAS28. Conclusions Elevated TLR-induced cytokines in RA monocytes were not related to ACPA or RF status. However, TLR1/2-induced IL-6 was associated with disease activity.
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Verney, Aurélie, Alexandra Traverse-Glehen, Evelyne Callet-Bauchu, Francoise Berger, Laurent Jallades, jean-Pierre Magaud, Pascale Felman, Gilles Andre Salles, and Lucile Baseggio. "Toll-Like Receptor Profiles In Splenic Marginal Zone B-Cell Lymphoma and Splenic Diffuse Red Pulp B-Cell Lymphoma." Blood 122, no. 21 (November 15, 2013): 3009. http://dx.doi.org/10.1182/blood.v122.21.3009.3009.
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Abstract Introduction Among recently discovered B cell activators responsible for signaling events leading to B-cell activation and maturation, of particular interest are the Toll-like receptors (TLRs). TLR expression is heterogeneous and variable among B-cells. In addition, abnormal TLR levels/signaling may play an important role in the pathogenesis of lymphoma, particularly in splenic marginal zone lymphoma (SMZL), since TLR pathways are recurrently targeted by genetic changes in this lymphoma. Methods Frozen spleen tissue specimens from patients with SMZL (n=13) and splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL, n=5) were analyzed for the expression of TLR1 to TLR10 in comparison to control cases (traumatic spleen, n=7) using multi-parametric flow cytometry and quantitative mRNA Taqman assay. To identify the B-cell subset, the samples were also stained with anti-CD19 and anti-CD3. All cases were studied by morphological, immunological, cytogenetic and molecular analysis. Results The TLR profile obtained at protein level by flow cytometry was closely related to that obtained at mRNA level. The SMZL/SDRPL B-cells expressed all TLRs, but with variable levels of protein expression (low for TLR1, TLR2, TLR3, TLR8, TLR9, TLR10, and high for TLR4, TLR5, TLR6 and TLR7). On the other hand, distinct TLRs profiles were observed according lymphoma subtypes. The SDRPL cases showed indeed a significant TLR2 under-expression and TLR4/TLR7 over-expression in comparison to SMZL cases and control B-cells. SMZL cases exhibited a significant TLR4/TLR8 over-expression in comparison to control B-cells. These TLR profiles were not associated with specific cytogenetic features (presence of del7q or trisomy 3) and/or immunological profile (expression of the CD11c/CD27/isotype of immunoglobulin). But, in both entities, TLR4 expression was higher in cases with mutated IGHV than in cases with unmutated IGHV. The overexpression of TLR7 MyD88-dependent signaling molecules has been reported as pathogenic mechanism for autoimmune diseases; however no more autoimmune disease or circulating auto-antibodies were associated with SDRPL cases as compared to SMZL cases. As previously reported, all cases but one SMZL case presented unmutated MyD88 (L265P mutation), and MyD88 protein evaluated here by flow cytometry was similarly expressed in both entities. While TLR7 stimulation is known to induce CD38 expression, all SDRPL cases were CD38 negative; while in SMZL cases, higher TLR7 expression was observed in CD38 positive as compared to CD38-negative cases. This may suggest the existence of an abnormal TLR7 pathway in SDRPL as opposed to SMZL. Conclusion TLR profiling should allow a better understanding of the mechanisms involved in SMZL/SDRPL pathogenesis. Present data suggest an abnormal TLR pathway involving NF-kB and/or MyD88 in the SDRPL entities. Disclosures: No relevant conflicts of interest to declare.
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Liu, Yuying, Limin Zhu, Nicole Y. Fatheree, Xiaoqin Liu, Susan E. Pacheco, Nina Tatevian, and Jon Marc Rhoads. "Changes in intestinal Toll-like receptors and cytokines precede histological injury in a rat model of necrotizing enterocolitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 3 (September 2009): G442—G450. http://dx.doi.org/10.1152/ajpgi.00182.2009.
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It is unclear whether the broad inflammatory response shown in neonatal necrotizing enterocolitis (NEC) is the cause or the effect of tissue injury. Toll-like receptors (TLRs) on intestinal dendritic, mononuclear, and epithelial cells recognize bacterial ligands and damaged tissues, thus activating the inflammatory response. The present study aimed to determine whether active TLR signaling would precede histological injury in NEC. Newborn rat pups were divided into four groups: dam fed, dam fed-hypoxic, formula fed, and formula fed-hypoxic (NEC). The ileal tissues were evaluated for NEC scores at 24, 48, 72, and 120 h. Quantitative real-time reverse transcription-polymerase chain reaction and immunohistochemistry were used to measure and localize intestinal TLRs. Cytokines were assessed by a multispot cytokine array. Among the four groups, ileal injury was seen only after 72 h of formula feeding and hypoxia. We found selective induction of mRNA levels in NEC compared with dam-fed controls for TLR2 > TLR4 > TLR1 = TLR3, TLR7, and TLR9 > TLR6 ( P < 0.01); TLR5 was downregulated ( P < 0.01). All TLR changes started at 48 h, before any histological evidence of NEC. Both Th1-type cytokines (IFN-γ, IL-1β, TNF-α, and KC/GRO) and Th2-type cytokines (IL-4, IL-5 and IL-13) were significantly increased in NEC but also in nondamaged formula-fed rat ileum. In conclusion, the intestinal expression of TLRs and cytokines precedes histological injury in the experimental NEC.
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Skert, Cristina, Manuela Fogli, Simone Perucca, Simona Fiorentini, Emirena Garrafa, Carla Filì, Annalisa Peli, et al. "Expression of Toll-Like Receptors on Peripheral Blood Cells After Allogeneic Stem Cell Transplantation: Results of a Prospective Study,." Blood 118, no. 21 (November 18, 2011): 4071. http://dx.doi.org/10.1182/blood.v118.21.4071.4071.
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Abstract Abstract 4071 Introduction. Emerging trends emphasize the importance of both innate and adaptive immune system in the response against infections, and in the pathogenesis of autoimmune and graft-versus-host (GVHD) diseases. Pattern recognition receptors such as Toll-like receptors (TLRs) play a key role in the cross-talk between innate and adaptive immune system. TLRs belong to type I transmembrane glycoprotein receptor family and recognize pathogen-associated molecular patterns (PAMPs), such as common protein, carbohydrate or DNA/RNA pattern motifs. TLRs are also receptors for endogenous ligands and damaged tissue, suggesting that both pathogen-derived molecules and products of damaged tissue can trigger signals which are responsible for the regulation of innate and adaptive immune responses. Extracellular ligands are recognized by surface TLRs (TLR1,TLR2,TLR4,TLR5, and TLR6). Intracellular TLRs (TLR3,TLR7,TLR8 and TLR9) bind mainly to foreign nucleic acids and sometimes detect self DNA/RNA. Aim of the study. Very little is known about expression and function of TLRs in vivo in patients who underwent allogeneic stem cell transplantation (SCT). The aim of this study was to evaluate the expression of TLRs on lymphocytes and monocytes in relation to the onset of acute GVHD. Methods. The expression of TLRs on lymphocytes and monocytes was analysed by flow cytometry as mean fluorescence intensity at day +30 and at the onset of GVHD. Functional data were obtained by ELISA assay after TLRs activation. The cell supernatants were collected and assayed for TNF-alpha, IFN-gamma and MCP-1. Relative induction of these cytokines was calculated in relation with unstimulated controls. Results. We analyzed 17 healthy donors and 34 patients. Median age was 46 years (range, 22–64) and 22 patients were male. Acute GVHD developed in 19 patients (12 with grade >=2). Clinical and transplant characteristics did not differ in patients with and without GVHD. Lymphocytes and monocytes of patients with acute GVHD showed higher levels of TLR5 (3,5±2,3 vs1,9±1,6 p=0,03; 25,8±25,9 vs 9,0±5,0 p=0,02) and a decreased expression of TLR1 (2,5±2,8 vs 4,3±2,8 p=0,02; 21,4±21,9 vs 54,9±37,4 p=0,005) and TLR9 (63,8±30,4 vs 111,1±62,9 p=0,03; 85,3±73,9 vs 164,2±90,6 p=0,01). IFN-gamma relative induction post-stimulation of TLR2,3,4 and 9 was significantly decreased in patients with acute GVHD (p< 0,04). Conclusions. TLRs show a different profile of expression in patients with acute GVHD in comparison with patients without it. These results suggest that the innate immune response via TLRs activation could be involved in the development of GVHD. In particular, a decreased expression of TLR-9 (receptor of hypomethylated DNA) on lymphocytes and monocytes can promote TLR-7 activation, inducing type I interferons and other pro-inflammatory cytokines. TLR-1 and −5, which are ligands for bacterial cell wall, could also be involved in the pathogenesis of GVHD. Moreover, acute GVHD negatively correlates with IFN-gamma production upon TLR2,3,4 and 9 activation. The assessment of a larger number of patients could be useful to understand the complex interplay among pathogens, self or non-self DNA and RNA, and the immune system. Disclosures: No relevant conflicts of interest to declare.
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Torok, Anastasia M., Amy H. Bouton, and Joanna B. Goldberg. "Helicobacter pylori Induces Interleukin-8 Secretion by Toll-Like Receptor 2- and Toll-Like Receptor 5-Dependent and -Independent Pathways." Infection and Immunity 73, no. 3 (March 2005): 1523–31. http://dx.doi.org/10.1128/iai.73.3.1523-1531.2005.
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ABSTRACT Helicobacter pylori is an important human pathogen that causes gastritis and is strongly associated with gastric ulcers, gastric adenocarcinomas, and mucosa-associated lymphoid tissue lymphomas. In response to H. pylori, interleukin-8 (IL-8) is secreted from host cells to attract components of the innate and adaptive immune systems to the site of infection. Toll-like receptor 2 (TLR2) and TLR5 have been shown to recognize H. pylori and to initiate signaling pathways that result in enhanced activation of NF-κB. Here, we evaluated the contribution of mitogen-activated protein kinase signaling pathways to TLR2-dependent and TLR5-dependent secretion of IL-8. Secretion of IL-8 from H. pylori-infected HEK293 cells was augmented by the expression of TLR2 or TLR5. While H. pylori infection resulted in the activation of ERK, JNK, and p38, the enhanced IL-8 secretion from TLR2- and TLR5-expressing cells coincided with increased p38 activation and phosphorylation of the transcription factor ATF2. When p38 activity was inhibited in TLR2- or TLR5-expressing cells, H. pylori-dependent IL-8 secretion returned to the level observed in infected parental HEK293 cells that did not express TLR2 or TLR5; inhibition of p38 had no effect on IL-8 secretion from infected parental HEK cells. In contrast, inhibition of JNK and/or ERK resulted in substantially less IL-8 secretion from infected cells, independent of TLR2 or TLR5 expression. Based on these data, we propose that H. pylori induces IL-8 secretion through a dual mechanism that includes a TLR2/5-independent component involving the activities of JNK and ERK and a TLR2/5-dependent component that requires p38 activity.
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Dlugosz, Aldona, Katherina Zakikhany, Nathalie Acevedo, Mauro D’Amato, and Greger Lindberg. "Increased Expression of Toll-Like Receptors 4, 5, and 9 in Small Bowel Mucosa from Patients with Irritable Bowel Syndrome." BioMed Research International 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/9624702.
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The aim of our study was to compare patients with irritable bowel syndrome (IBS) and healthy controls regarding the expression of toll-like receptors 2, 4, 5, and 9 (TLR2, TLR4, TLR5, and TLR9), the primary mucosal receptors of bacterial components, in small and large bowel mucosa.Methods.We analysed biopsies from jejunum and sigmoid colon of 22 patients (17 females) with IBS aged 18–66 (median: 39) years and 14 healthy volunteers (12 females) aged 22–61 (median: 42) years. Eight patients had constipation-predominant IBS (C-IBS), 7 had diarrhoea-predominant IBS (D-IBS), and 7 had IBS without predominance of constipation or diarrhoea. We analysed mRNA levels for TLRs using quantitative PCR and distribution of TLRs in mucosa using immunohistochemistry.Results.We found increased mRNA expression of TLR4 (mean fold change1.85±0.31versus1.0±0.20;p<0.05), TLR5 (1.96±0.36versus1.0±0.20;p<0.05) and TLR9 (2.00±0.24versus1.0±0.25;p<0.01) but not of TLR2 in the small bowel mucosa from patients with IBS compared to the controls. There was no significant difference in mRNA levels for TLRs in colon mucosa between patients and controls.Conclusion.Upregulation of TLR4, TLR5, and TLR9 suggests the involvement of bacteria or dysregulation of the immune response to commensal flora in small bowel mucosa in IBS patients.
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van der Houwen, Tim B., Willem A. Dik, Marco Goeijenbier, Manizhah Hayat, Nicole M. A. Nagtzaam, Martin van Hagen, and Jan A. M. van Laar. "Leukocyte toll-like receptor expression in pathergy positive and negative Behçet’s disease patients." Rheumatology 59, no. 12 (August 5, 2020): 3971–79. http://dx.doi.org/10.1093/rheumatology/keaa251.
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Abstract Objectives To investigate whether the auto-inflammatory nature and the pathergic reaction in Behçet’s disease (BD) are driven by a disturbed toll-like receptor (TLR) response. Methods We compared both TLR expression by flow-cytometry and TLR response by stimulation assay in 18 BD patients (both pathergy positive and pathergy negative) with 15 healthy controls. Results Expression of TLR1 and 2 was significantly elevated in B-lymphocytes of BD patients compared with healthy controls. TLR1, 2 and 4 were significantly more highly expressed in both CD4+ and CD8+ T-lymphocytes of BD patients. Granulocytes of BD patients displayed significantly higher expression of TLR1, 2, 4 and 6. TLR2, 4 and 5 expression was significantly increased on classical monocytes of BD patients. Intermediate monocytes of BD patients showed an increase in expression of TLR2. Furthermore, TLR2 and 5 were significantly more highly expressed in non-classical monocytes of BD patients. In pathergy positive patients, TLR5 was even more highly expressed compared with pathergy negative patients on B- and T-lymphocytes and granulocytes. Furthermore, TLR2 and 5 showed an elevated TNF-α response to stimulation with their cognate ligands. Conclusion Immune cells of BD patients overexpress TLR1, 2, 4, 5 and 6. Furthermore, after stimulation of TLR2 and 5, BD patients demonstrate a more potent TNF-α response. Although this is a small cohort, in the pathergy positive patients, TLR5 expression is even further augmented, suggesting that a microbial (flagellin) or damage (HMGB1) associated signal may trigger the exaggerated immune response that is characteristic for the pathergy phenomenon in BD. In conclusion, these results point to an exaggerated TLR response in the auto-inflammatory nature of BD.
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Andersen-Nissen, Erica, Kelly D. Smith, Richard Bonneau, Roland K. Strong, and Alan Aderem. "A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin." Journal of Experimental Medicine 204, no. 2 (February 5, 2007): 393–403. http://dx.doi.org/10.1084/jem.20061400.
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The molecular basis for Toll-like receptor (TLR) recognition of microbial ligands is unknown. We demonstrate that mouse and human TLR5 discriminate between different flagellins, and we use this difference to map the flagellin recognition site on TLR5 to 228 amino acids of the extracellular domain. Through molecular modeling of the TLR5 ectodomain, we identify two conserved surface-exposed regions. Mutagenesis studies demonstrate that naturally occurring amino acid variation in TLR5 residue 268 is responsible for human and mouse discrimination between flagellin molecules. Mutations within one conserved surface identify residues D295 and D367 as important for flagellin recognition. These studies localize flagellin recognition to a conserved surface on the modeled TLR5 structure, providing detailed analysis of the interaction of a TLR with its ligand. These findings suggest that ligand binding at the β sheets results in TLR activation and provide a new framework for understanding TLR–agonist interactions.
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Zhu, Ke-Cheng, Meng Wu, Dian-Chang Zhang, Hua-Yang Guo, Nan Zhang, Liang Guo, Bao-Suo Liu, and Shi-Gui Jiang. "Toll-Like Receptor 5 of Golden Pompano Trachinotus ovatus (Linnaeus 1758): Characterization, Promoter Activity and Functional Analysis." International Journal of Molecular Sciences 21, no. 16 (August 18, 2020): 5916. http://dx.doi.org/10.3390/ijms21165916.
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Toll-like receptors (TLRs), as important pattern recognition receptors, represent a significant component of fish immune systems and play an important role in resisting the invasion of pathogenic microorganisms. The TLR5 subfamily contains two types of TLR5, the membrane form of TLR5 (TLR5M) and the soluble form of TLR5 (TLR5S), whose detailed functions have not been completely elucidated. In the present study, we first identified two genes, TLR5M (ToTLR5M) and TLR5S (ToTLR5S), from golden pompano (Trachinotus ovatus). The full-length ToTLR5M and ToTLR5S cDNA are 3644 bp and 2329 bp, respectively, comprising an open reading frame (ORF) of 2673 bp, encoding 890 amino acids, and an ORF of 1935 bp, encoding 644 amino acids. Both the ToTLR5s possess representative TLR domains; however, only ToTLR5M has transmembrane and intracellular TIR domains. Moreover, the transcription of two ToTLR5s was significantly upregulated after stimulation by polyinosinic:polycytidylic acid (poly (I:C)), lipopolysaccharide (LPS), and flagellin in both immune-related tissues (liver, intestine, blood, kidney, and skin) and nonimmune-related tissue (muscle). Furthermore, the results of bioinformatic and promoter analysis show that the transcription factors GATA-1 (GATA Binding Protein 1), C/EBPalpha (CCAAT Enhancer Binding Protein Alpha), and ICSBP (Interferon (IFN) consensus sequence binding protein) may play a positive role in moderating the expression of two ToTLR5s. Overexpression of ToTLR5M and ToTLR5S notably increases NF-κB (nuclear factor kappa-B) activity. Additionally, the binding assay revealed that two rToTLR5s can bind specifically to bacteria and pathogen-associated molecular patterns (PAMPs) containing Vibrio harveyi, Vibrio anguillarum, Vibrio vulnificus, Escherichia coli, Photobacterium damselae, Staphylococcus aureus, Aeromonas hydrophila, LPS, poly(I:C), flagellin, and peptidoglycan (PGN). In conclusion, the present study may help to elucidate the function of ToTLR5M/S and clarify their possible roles in the fish immune response to bacterial infection.
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Ortega-Cava, Cesar F., Shunji Ishihara, Mohammad A. K. Rumi, M. M. Aziz, Hideaki Kazumori, Takafumi Yuki, Yoshiyuki Mishima, et al. "Epithelial Toll-Like Receptor 5 Is Constitutively Localized in the Mouse Cecum and Exhibits Distinctive Down-Regulation during Experimental Colitis." Clinical and Vaccine Immunology 13, no. 1 (January 2006): 132–38. http://dx.doi.org/10.1128/cvi.13.1.132-138.2006.
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ABSTRACT We recently demonstrated that the pattern recognition receptors (PRRs) toll-like receptor 2 (TLR2), TLR4, and CD14 are expressed in mouse colonic epithelium in a compartmentalized manner. Here we report the localization of TLR5, the receptor for bacterial flagellin, and its distinctive down-regulation during experimental colitis. Guts from normal BALB/c mice and those with dextran sodium sulfate (DSS)-induced colitis were compared. Each gut was divided into seven segments (stomach, small intestine [three parts], and colon [three parts]), and epithelial cells and crypt units were collected by scraping and EDTA treatment, respectively. Northern blotting showed that TLR5 mRNA was preferentially expressed in the epithelium of the proximal colon in normal mice. Laser capture microdissection coupled to reverse transcriptase PCR confirmed this localization. TLR5 protein expression reflected mRNA expression, as evidenced by Western blotting. In mice with acute colitis, inflammation occurred mainly in the distal colon. Interestingly, while TLR2, TLR4, and CD14 were up-regulated in the inflamed colon, TLR5 was down-regulated at both the mRNA and protein levels. Decreased TLR5 expression was more evident during chronic colitis. Additional in vitro studies using a mouse cell line, Colon-26, showed that gamma interferon (IFN-γ) time- and dose-dependently down-regulates TLR5. In conclusion, epithelial cells, mainly in the proximal colon, constitutively express TLR5. TLR5 expression is down-regulated in vivo during acute and chronic DSS-induced colitis, in contrast to the expression of TLR2, TLR4, and CD14. The mechanism governing TLR5 regulation may therefore differ from that controlling other PRRs. Finally, IFN-γ may be involved in down-regulating TLR5 expression.
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Rodríguez-Jorge, Otoniel, Linda A. Kempis-Calanis, Wassim Abou-Jaoudé, Darely Y. Gutiérrez-Reyna, Céline Hernandez, Oscar Ramirez-Pliego, Morgane Thomas-Chollier, Salvatore Spicuglia, Maria A. Santana, and Denis Thieffry. "Cooperation between T cell receptor and Toll-like receptor 5 signaling for CD4+ T cell activation." Science Signaling 12, no. 577 (April 16, 2019): eaar3641. http://dx.doi.org/10.1126/scisignal.aar3641.
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CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.
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Arvaniti, Eleni, Stavroula Ntoufa, Nikos Papakonstantinou, Tasoula Touloumenidou, Nikolaos Laoutaris, Achilles Anagnostopoulos, Kleoniki Lamnisou, et al. "Toll-Like Receptor Signaling Pathway In Chronic Lymphocytic Leukemia: Distinct Gene Expression Profiles of Potential Pathogenetic Significance In Specific Subsets of Patients." Blood 116, no. 21 (November 19, 2010): 44. http://dx.doi.org/10.1182/blood.v116.21.44.44.
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Abstract Abstract 44 The role of antigen in the development of CLL is underscored by the biased immunoglobulin (IG) gene repertoire expressed by the malignant clones, the prognostic implications of B-cell receptor (BcR) structure and the identification of subsets of patients with quasi-identical, stereotyped BcRs. The structural homology of BcRs implies a role for a limited set of antigens or structurally related epitopes in leukemogenesis. Antigen recognition and host defense rely on multiple mechanisms acting synergistically in order to mount an effective immune response. These include specific stimulation through the BcR and non-specific stimulation through innate immune receptors, of which the major class is the Toll-like receptor (TLR) family. The available data on TLR expression in CLL are limited and derive from small series of patients. In the present study we performed a systematic gene expression profiling of the TLR signaling pathway in a large series of 191 patients with CLL. The analysis extended from all TLRs known to be functional in normal B cells to adaptors, effectors, inhibitors and members of the NFKB, JNK/p38, NF/IL6, and IRF signaling pathways downstream of TLR signaling. In addition, differences in gene expression profiles were sought for among subgroups of cases defined by BcR molecular features, such as the repertoire and mutational status of the IG heavy variable (IGHV) genes or the expression of stereotyped BcRs. CD19+ B lymphocytes were negatively selected from peripheral blood samples. The gene expression profile of the TLR signalling pathway was determined by the RT2Profiler™ PCR Array kit (PAHS-018A array, SABiosciences). At cohort level, among the receptors, high expression was recorded for TLR7 and CD180, intermediate for TLR1, TLR6 and TLR10 and low expression for TLR2 and TLR9. TLR4 and TLR8 were characterized by low to undetectable expression, with significant variations between patients, while TLR3 and TLR5 were not expressed in any case. The vast majority of the adaptors (e.g. MyD88, TICAM1, TRAF6), the effectors (UBE2N) and the members of the NFKB, JNK/p38, NF/IL6, and IRF signaling pathways downstream of TLR signaling were intermediately to highly expressed, while the inhibitors of TLR activity (TOLLIP, SIGIRR/TIR8) were generally low to undetectable, suggesting that the TLRs signalling pathway is active in CLL. Further comparison in subgroups of cases carrying mutated vs. unmutated IGHV sequences (124 and 67 cases, respectively) revealed upregulation of CD80, CD86, IL6, IFNG and TLR4 and downregulation of TLR8 and NFKBIL1 in the mutated subgroup. Significant differences in gene expression profiles were also found in subgroups of cases with stereotyped receptors. Comparison of subset #4 (mutated IGHV4-34/1GKV2-30 BcR, 10 cases) vs. subset #1 (unmutated IGHV1/5/7-IGKV1(D)-39 BcR, 10 cases) vs. subset #8 (unmutated IGHV4-39/IGKV1(D)-39 BcR, 4 cases) revealed: (i) upregulation of TLR7 and NFKB1A and downregulation of CD86 and TLR4 in #1 vs #4 cases; (ii) upregulation of MAP4K4 and TLR4 and downregulation of NFKB1A and CD180 in #8 vs #1 cases; and, (iii) upregulation of LY96 and downregulation of RIPK2 and CD86 in #8 vs #4 cases. In conclusion, the TLR gene expression profile of CLL is consistent with derivation from antigen-experienced B cells. Significant variations were identified in different subgroups of cases defined by BcR molecular features, indicating distinctive activation patterns of the TLR signaling pathway, especially among cases assigned to subsets with stereotyped BcRs, with potential implications about the nature of the antigenic stimulation. Disclosures: No relevant conflicts of interest to declare.
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Rezasoltani, Sama, Reza Ghanbari, Mehdi Azizmohammad Looha, Ehsan Nazemalhosseini Mojarad, Abbas Yadegar, Delisha Stewart, Hamid Asadzadeh Aghdaei, and Mohammad Reza Zali. "Expression of Main Toll-Like Receptors in Patients with Different Types of Colorectal Polyps and Their Relationship with Gut Microbiota." International Journal of Molecular Sciences 21, no. 23 (November 26, 2020): 8968. http://dx.doi.org/10.3390/ijms21238968.
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Abnormal activation of Toll-like receptor (TLRs) signaling can result in colon cancer development. The aim of this study was to investigate the expression of important TLRs in different histological types of colorectal polyps and evaluate their relationship with intestinal microbiota. The expression levels of TLR2, 3, 4, and 5 were analyzed in intestinal biopsy specimens of 21 hyperplastic polyp (HP), 16 sessile serrated adenoma (SSA), 29 tubular adenoma (TA), 21 villous/tubulovillous (VP/TVP) cases, and 31 normal controls. In addition, selected gut bacteria including Streptococcus bovis, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Fusobacterium nucleatum, Porphyromonas spp., Lactobacillus spp., Roseburia spp., and Bifidobacterium spp. were quantified in fecal samples using absolute qRT PCR, and, finally, the association between TLRs and these gut microbiota- was evaluated by Spearman’s correlation coefficient. Higher expression of TLR2 and TLR4 in VP/TVP and TA, and lower expression levels of TLR3 and TLR5 in all type of polyps were observed. The differences in TLR expression patterns was not only dependent on the histology, location, size, and dysplasia grade of polyps but also related to the intestinal microbiota patterns. TLR2 and TLR4 expression was directly associated with the F. nucleatum, E. faecalis, S. bovis, Porphyromonas, and inversely to Bifidobacterium, Lactobacillus, and Roseburia quantity. Furthermore, TLR3 and TLR5 expression was directly associated with Bifidobacterium, Roseburia, and Lactobacillus quantity. Our results suggest a possible critical role of TLRs during colorectal polyp progression. An abnormal regulation of TLRs in relation to gut microbial quantity may contribute to carcinogenesis.
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Shin, Ok S., Ralph R. Isberg, Shizuo Akira, Satoshi Uematsu, Aruna K. Behera, and Linden T. Hu. "Distinct Roles for MyD88 and Toll-Like Receptors 2, 5, and 9 in Phagocytosis of Borrelia burgdorferi and Cytokine Induction." Infection and Immunity 76, no. 6 (March 31, 2008): 2341–51. http://dx.doi.org/10.1128/iai.01600-07.
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ABSTRACT The contribution of Toll-like receptors (TLRs) to phagocytosis of Borrelia burgdorferi has not been extensively studied. We show that bone marrow-derived macrophages (BMDM) from MyD88−/− mice or Raw cells transfected with a dominant-negative MyD88 were unable to efficiently internalize B. burgdorferi. Knockouts of TLR2 and TLR9 or knockdown of TLR5 by small interfering RNA produced no defects in phagocytosis of B. burgdorferi. Production of inflammatory cytokines was greatly diminished in MyD88−/− BMDM but only partially affected in TLR2−/− BMDM or knockdown of TLR5 and unaffected in TLR9−/− BMDM. Cytochalasin D reduced cytokine induction, but not to the level of the MyD88−/− BMDM. Addition of cytochalasin D to TLR2−/− BMDM inhibited inflammatory responses to B. burgdorferi to the level of MyD88−/− BMDM, consistent with a role for TLR2 in both recognition of extracellular products and lysosomal sampling by TLR2 after processing of the organism. Cytochalasin D had no impact on cytokine production in cells undergoing TLR5 knockdown. These results suggest that MyD88, but not TLR2, TLR5, and TLR9, is important for the uptake of B. burgdorferi and that MyD88 affects inflammatory responses through both its effects on phagocytosis and its role in transducing signals from TLR2 and TLR5.
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Voogdt, Carlos G. P., Jaap A. Wagenaar, and Jos P. M. van Putten. "Duplicated TLR5 of zebrafish functions as a heterodimeric receptor." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): E3221—E3229. http://dx.doi.org/10.1073/pnas.1719245115.
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Toll-like receptor 5 (TLR5) of mammals, birds, and reptiles detects bacterial flagellin and signals as a homodimeric complex. Structural studies using truncated TLR5b of zebrafish confirm the homodimeric TLR5–flagellin interaction. Here we provide evidence that zebrafish (Danio rerio) TLR5 unexpectedly signals as a heterodimer composed of the duplicated gene products drTLR5b and drTLR5a. Flagellin-induced signaling by the zebrafish TLR5 heterodimer increased in the presence of the TLR trafficking chaperone UNC93B1. Targeted exchange of drTLR5b and drTLR5a regions revealed that TLR5 activation needs a heterodimeric configuration of the receptor ectodomain and cytoplasmic domain, consistent with ligand-induced changes in receptor conformation. Structure-guided substitution of the presumed principal flagellin-binding site in human TLR5 with corresponding zebrafish TLR5 residues abrogated human TLR5 activation, indicating a species-specific TLR5–flagellin interaction. Our findings indicate that the duplicated TLR5 of zebrafish underwent subfunctionalization through concerted coevolution to form a unique heterodimeric flagellin receptor that operates fundamentally differently from TLR5 of other species.
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Jarchum, Irene, Mingyu Liu, Lauren Lipuma, and Eric G. Pamer. "Toll-Like Receptor 5 Stimulation Protects Mice from AcuteClostridium difficileColitis." Infection and Immunity 79, no. 4 (January 18, 2011): 1498–503. http://dx.doi.org/10.1128/iai.01196-10.
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ABSTRACTClostridium difficileis a spore-forming bacterium that infects the lower intestinal tract of humans and is the most common known cause of diarrhea among hospitalized patients.Clostridium difficilecolitis is mediated by toxins and develops during or following antibiotic administration. We have used a murine model ofC. difficileinfection, which reproduces the major features of the human disease, to study the effect of innate immune activation on resistance toC. difficileinfection. We found that administration of purifiedSalmonella-derived flagellin, a Toll-like receptor 5 (TLR5) agonist, protects mice fromC. difficilecolitis by delayingC. difficilegrowth and toxin production in the colon and cecum. TLR5 stimulation significantly improves pathological changes in the cecum and colon ofC. difficile-infected mice and reduces epithelial cell loss. Flagellin treatment reduces epithelial apoptosis in the large intestine, thereby protecting the integrity of the intestinal epithelial barrier duringC. difficileinfection. We demonstrate that restoring intestinal innate immune tone by TLR stimulation in antibiotic-treated mice ameliorates intestinal inflammation and prevents death fromC. difficilecolitis, potentially providing an approach to preventC. difficile-induced pathology.
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Li, Hai-tao, Liang Wang, Di Liu, and Xiu-qin Yang. "Characterization and functional significance of polymorphisms in porcine Toll-like receptor (TLR) 5 gene." Canadian Journal of Animal Science 92, no. 4 (December 2012): 409–15. http://dx.doi.org/10.4141/cjas2012-034.
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Li, H.-t., Wang, L., Liu, D. and Yang, X.-q. 2012. Characterization and functional significance of polymorphisms in porcine Toll-like receptor (TLR) 5 gene. Can. J. Anim. Sci. 92: 409–415. Toll-like receptor (TLR) 5 plays an important role in host defenses by recognizing bacterial flagellin and signaling to initiate immune responses. Polymorphisms in the TLR5 gene have a profound influence on receptor function and host susceptibility/resistance to infectious disease, as suggested by studies in humans and other species. In the present study, we characterized polymorphisms and determined their functional significance in the porcine TLR5 gene. Four novel non-synonymous single nucleotide polymorphisms (SNPs), c.176C>T (p.R59M), c.902C>T (p.S301F), c.959T>A (p.F320Y), and c.1796C>T (p.T599M) (reference sequence: GenBank No. AB208697), were first identified by sequencing the complete coding sequences (CDS) of the TLR5 gene in the Min pig, an indigenous Chinese pig breed known for its high general resistance to disease. SNP c.1796C>T (p.T599M) is located in one of the six predicted N-glycosylation sites in the extracellular domain of the TLR5 protein. By measuring protein activation, as represented by nuclear factor κB activity, in transiently transfected PK-15 cells with TLR5 expression vectors carrying site-directed mutations, we demonstrated that the previously discovered SNP c.1205C>T, leading to the amino acid substitution of proline by leucine, attenuated the responses of the receptor to flagellin (P<0.01). Further functional investigation on SNP c.1205C>T is necessary to determine its possible role in disease susceptibility in pigs and may facilitate pig breeding aimed at improving disease resistance.
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Kim, W. Y., J. W. Lee, J. J. Choi, C. H. Choi, T. J. Kim, B. G. Kim, S. Y. Song, and D. S. Bae. "Increased expression of Toll-like receptor 5 during progression of cervical neoplasia." International Journal of Gynecologic Cancer 18, no. 2 (2008): 300–305. http://dx.doi.org/10.1111/j.1525-1438.2007.01008.x.
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The purpose of this study was to determine whether Toll-like receptor 5 (TLR5) expression was associated with disease progression in cervical neoplasia. TLR5 expression was evaluated by immunohistochemistry (IHC) in 55 formalin-fixed paraffin-embedded cervical tissues; 10 normal cervical specimens, 9 low-grade cervical intraepithelial neoplasias (CINs), 12 high-grade CINs, and 24 invasive squamous cell carcinomas (ISCCs). TLR5 expression was also evaluated at the RNA level, in fresh, frozen cervical carcinoma tissues by real-time quantitative RT-PCR. TLR5 expression, which was mainly observed as cytoplasmic staining, gradually increased in accordance with the histopathologic grade in the following order: low-grade CIN less than high-grade CIN less than ISCC (P< 0.001). Immunohistochemical staining showed that TLR5 expression was undetectable (80%) or weak (20%) in normal cervical squamous epithelial tissues. However, moderate expression was detected in 33.3% of low-grade CIN (3/9), 41.7% of high-grade CIN (5/12), and 45.8% of ISCC (11/24). Strong expression was detected in as much as 33.3% of high-grade CIN (4/12) and 50% of ISCC (12/24). Contrary to IHC results, real-time quantitative RT-PCR revealed that TLR5 expression in tumors was not statistically different compared to normal cervical tissues (P= 0.1452). The IHC result suggests that TLR5 may play a significant role in tumor progression of cervical neoplasia and may represent a useful marker for malignant transformation of cervical squamous cells.
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Freedman, Jane. "Toll-Like Receptors: Mechanism and Relation to Human Populations." Blood 128, no. 22 (December 2, 2016): SCI—46—SCI—46. http://dx.doi.org/10.1182/blood.v128.22.sci-46.sci-46.
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Abstract Inflammation and infection are known to alter platelet count, production, and function and major studies have demonstrated that acute infection is associated with a transient 5-fold increased risk of thrombotic vascular syndromes including stroke, acute myocardial infarction, and peripheral vascular occlusion. Platelets play an intricate role in thrombosis, myocardial infarction, and thrombotic stroke and are now being appreciated for their functional innate immune receptors. More recently, platelets have been connected to the host's immune system via their ability to trap bacteria and present them to leukocytes for destruction. This interaction appears crucial to the host's immune defense. Platelets are known to express functional interleukin 1 receptor (IL1R), toll like receptor (TLR)2, TLR3, TLR4, TLR7, and TLR9 with other immune receptors under investigation. It is known that activation of TLR2, TLR7, or TLR4 leads to platelet-neutrophil interaction.Platelet-leukocyte communication has also been observed during different bacterial or viral infections. We have used animal models and large-scale human clinical data to examine if platelets demonstrate specific immunity or broadly express TLRs and characterize how this expression is causative in immune responses. Our studies have included thousands of participants of the Framingham Heart Study in addition to investigations of active infection and inflammatory diseases. We have also examined if presence of immune receptors in platelets is associated with vascular inflammation and cardiovascular disease or risk factors. We have found widespread and varied immune and inflammatory platelet receptor and gene expression that varies remarkably between individuals and diseases. Additionally, anucleate platelets contain transcripts that might relate to other physiological or pathophysiological conditions and are known to be released into the circulation, participate in protein formation, and engage in horizontal RNA transfer to other vascular cells. These platelet transcripts include microRNAs (miRNAs), which are small noncoding RNAs involved in many molecular processes, most notably regulation of gene expression and release of these noncoding RNAs also may be regulated by innate immune receptors. In platelets and their released exosomes, these noncoding RNAs seem to participate in vascular homeostasis, inflammation, and platelet immune function. In addition, they are associated with the presence or extent of cardiovascular diseases, such as atrial fibrillation and peripheral vascular disease. Thus, platelets are known to contain a myriad of receptors that regulate hemostasis and thrombosis; however, there is growing appreciation of the diverse expression of receptors traditionally associated with immune and inflammatory cells. Disclosures No relevant conflicts of interest to declare.
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Madrazo, Denise R., Susanne L. Tranguch, and Ian Marriott. "Signaling via Toll-Like Receptor 5 Can Initiate Inflammatory Mediator Production by Murine Osteoblasts." Infection and Immunity 71, no. 9 (September 2003): 5418–21. http://dx.doi.org/10.1128/iai.71.9.5418-5421.2003.
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ABSTRACT Murine osteoblasts express Toll-like receptor 5 (TLR5), and this expression is upregulated following exposure to bacteria or to the TLR5 agonist, flagellin. Importantly, flagellin activates transcriptional regulators and elicits proinflammatory cytokine production, suggesting TLR5 functionality. TLR5 may represent an important mechanism underlying the recognition of bacterial pathogens by osteoblasts during bone infections.
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Alan, Emel, and Narin Liman. "Toll-like receptor expression patterns in the rat uterus during post partum involution." Reproduction, Fertility and Development 30, no. 2 (2018): 330. http://dx.doi.org/10.1071/rd16431.
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Toll-like receptors (TLRs) belong to a family of pathogen recognition receptors and play critical roles in detecting and responding to invading pathogens. TLR expression could be significant because, in the uterus, the reproductive tract is an important site of exposure to and infection by pathogens during the post partum involution period. To clarify the expression and localisation patterns of TLRs in the rat uterus on Days 1, 3, 5 and 10 post partum (PP1, PP3, PP5 and PP10 respectively), immunohistochemistry and western blotting were used to analyse TLR1–7, TLR9 and TLR10. The immunohistochemistry results indicated that TLR1–7, TLR9 and TLR10 were localised in both the cytoplasm and nuclei of luminal and glandular epithelium, stromal fibroblasts and myometrial cells in the rat uterus. In the luminal epithelium, TLR4–7 were also found in lateral membranes, whereas TLR10 was present in apical membranes. Western blot analysis revealed that the expression of TLR proteins increased with the number of days post partum, reaching a maximum on PP10, although levels did not differ significantly from those on PP1 (P > 0.05). These findings confirm that TLR1–7, TLR9 and TLR10 are constitutively expressed in uterine cells and that localisation pattern of TLRs in the endometrium varies with structural changes in the uterus on different days of involution. These results suggest that TLRs may play a role in uterine repair and remodelling during physiological involution.
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Bernardino, Andrea L. F., Tereance A. Myers, Xavier Alvarez, Atsuhiko Hasegawa, and Mario T. Philipp. "Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis." Infection and Immunity 76, no. 10 (August 11, 2008): 4385–95. http://dx.doi.org/10.1128/iai.00394-08.
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ABSTRACT Lyme neuroborreliosis is likely caused by inflammatory effects of the tick-borne spirochete Borrelia burgdorferi on the nervous system. Microglia, the resident macrophage cells within the central nervous system (CNS), are important in initiating an immune response to microbial products. In addition, astrocytes, the major CNS glial cell type, also can contribute to brain inflammation. TLRs (Toll-like receptors) are used by glial cells to recognize pathogen-associated molecular patterns (PAMPs), mediate innate responses, and initiate an acquired immune response. Here we hypothesize that because of their PAMP specificities, TLR1, -2, -5, and -9 may be involved in the pathogenesis of Lyme neuroborreliosis. Previous reports have shown that the rhesus monkey is the only animal model to exhibit signs of Lyme neuroborreliosis. Therefore, we used primary cultures of rhesus astrocytes and microglia to determine the role of TLRs in mediating proinflammatory responses to B. burgdorferi. The results indicate that microglia and astrocytes respond to B. burgdorferi through TLR1/2 and TLR5. In addition, we observed that phagocytosis of B. burgdorferi by microglia enhances not only the expression of TLR1, -2, and -5, but also that of TLR4. Taken together, our data provide proof of the concept that astrocyte and microglial TLR1, -2, and -5 are involved in the in vivo response of primate glial cells to B. burgdorferi. The proinflammatory molecules elicited by these TLR-mediated responses could be a significant factor in the pathogenesis of Lyme neuroborreliosis.
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Shindo, Maki, Xueqing Liang, Zhimei Wang, Jeffery S. Miller, Martin Carroll, and Wei Chen. "Toll-Like Receptor Agonists Induce Immunogeneicity and Apoptosis of Acute Myeloid Leukemia Cells." Blood 110, no. 11 (November 16, 2007): 160. http://dx.doi.org/10.1182/blood.v110.11.160.160.
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Abstract Acute myeloid leukemia (AML) is a common form of acute leukemia and remains a difficult disease with poor survival in patients who have failed standard therapy. New therapeutic strategies are needed to achieve longer survival and improve cure rates in AML patients. Toll-like receptor (TLR) agonists have been shown to elicit anti-leukemia effects in murine AML models. However, TLR expression profile of human AML cells is unknown. We analyzed TLR1-10 mRNA expression in purified AML cells from 41 patients with different AML subtypes (M0, M1, M2, M3, M4, or M5; n > 5 per group) by real-time RT-PCR. The majority of AML samples expressed high level of TLR2, 4, 7, 8, low level of TLR1, 5, 9, 10, and undetectable level of TLR3. Significant higher TLR4 and TLR7 expressions were detected on M4 and M5 subtypes of AML cells. Triggering TLR4 or TLR7 with specific TLR agonists (Monophosphoryl Lipid A or Imiquimod) significantly increased the surface expression of molecules essential for T cell activation (CD54, CD80, CD86) on AML M4/M5 cells and enhanced T-cell mediated proliferative responses against AML cells. Thus, TLR signaling enhances the immunogenicity of AML M4/M5 cells and makes them more suitable targets for T cell mediated attack. Most importantly, TLR7 agonist strongly induced apoptotic death of primary AML M4/M5 cells and inhibited the growth of TLR7-expressing AML cell lines (U937, HL-60, KG-1) in culture in a drug dose dependent manner. The addition of TLR7 agonist at 10 ug/ml fully induced apoptosis of AML cells and inhibited the growth of AML cell lines, as confirmed by viable cell counts and TMRE staining. Intracellular staining demonstrated that TLR7 agonist treatment significantly down-regulated the signal transducer and activator of transcription (STAT)3 and STAT5 protein expression in AML cells. These results suggest that TLR7 agonist-induced apoptosis of AML cells is likely via inhibition of STAT3 and/or STAT5 signaling pathway. To study the in vivo effects of TLR7 agonist against human AML cells, primary AML M4/M5 cells or a monocytic AML cell line (U937) were injected i.p. into NOD-SCID IL2Rgamma<null> mice with or without subsequent TLR7 agonist treatment. Mice receiving TLR7 agonist treatment (1 mg/kg daily i.p. infusion for 5 days) significantly reduced tumor burden with substantially lower numbers of engrafted leukemia cells detected in these xenograft mice. Flow cytometry results confirmed that residual AML cells recovered from mice treated with TLR7 agonist were apoptotic with down-regulated expression of TMRE and STAT3/STAT5, confirming previous in vitro findings that TLR7 agonist-treated AML cells are programmed to die. The antitumor efficacy of systemic administration of TLR7 agonist in NOD/SCID mice with established human AML is being investigated using these xenograft mouse models. In summary, our results provide the first report of TLR expression profile of human AML cells and demonstrate that TLR targeting of AML cells can increase the immunogeneicity of leukemia cells and directly induce AML apoptosis in vitro and in vivo, providing new insights into the biology and therapy of AML.
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DeCarlo, Correne A., Bruce Rosa, Robert Jackson, Sarah Niccoli, Nicholas G. Escott, and Ingeborg Zehbe. "Toll-Like Receptor Transcriptome in the HPV-Positive Cervical Cancer Microenvironment." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/785825.
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The human papillomavirus (HPV) directly infects cervical keratinocytes and interferes with TLR signalling. To shed light on the effect of HPV on upstream receptors, we evaluated TLRs 1–9 gene expression in HPV-negative normal and HPV-positive pre-malignant and malignantex vivocervical tissue. Quantitative real-time polymerase chain reaction was performed separately for epithelial and stromal tissue compartments. Differences in gene expression were analyzed by the Jonckheere-Terpstra trend test or the Student'st-test for pairwise comparison. Laser capture microdissection revealed an increase in TLR3 and a decrease in TLR1 mRNA levels in dysplastic and carcinoma epithelium, respectively. In the stroma, a trend of increasing TLR 1, 2, 5, 6, and 9 mRNA levels with disease severity was found. These findings implicate the involvement of TLR3 and TLR1 in early and late cervical carcinogenesis, respectively, suggesting that stromal upregulation of TLRs may play a role in cervical disease progression.
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Keating, Sinead E., Geraldine M. Maloney, Ellen M. Moran, and Andrew G. Bowie. "IRAK-2 Participates in Multiple Toll-like Receptor Signaling Pathways to NFκB via Activation of TRAF6 Ubiquitination." Journal of Biological Chemistry 282, no. 46 (September 18, 2007): 33435–43. http://dx.doi.org/10.1074/jbc.m705266200.
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Toll-like receptor (TLR) signaling is known to involve interleukin-1 receptor-associated kinases (IRAKs), however the particular role of IRAK-2 has remained unclear. Further, although IRAK-1 was originally thought to be central for the TLR-NFκB signaling axis, recent data have shown that it is dispensable for NFκB activation for some TLRs and demonstrated an alternative role for it in interferon regulatory factor activation. Here we show that IRAK-2 is critical for the TLR-mediated NFκB activation pathway. The poxviral TLR antagonist A52 inhibited NFκB activation by TLR2, -3, -4, -5, -7, and -9 ligands, via its interaction with IRAK-2, while not affecting interferon regulatory factor activation. Knockdown of IRAK-2 expression by small interfering RNA suppressed TLR3, TLR4, and TLR8 signaling to NFκB in human cell lines, and importantly, TLR4-mediated chemokine production in primary human cells. IRAK-2 usage by different TLRs was distinct, because it acted downstream of the TLR adaptors MyD88 and Mal but upstream of TRIF. Expression of IRAK-2, but not IRAK-1, led to TRAF6 ubiquitination, an event critical for NFκB activation. Further, IRAK-2 loss-of-function mutants, which could not activate NFκB, were incapable of promoting TRAF6 ubiquitination. Thus we propose that IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NFκB.
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Morris, Amy E., H. Denny Liggitt, Thomas R. Hawn, and Shawn J. Skerrett. "Role of Toll-like receptor 5 in the innate immune response to acute P. aeruginosa pneumonia." American Journal of Physiology-Lung Cellular and Molecular Physiology 297, no. 6 (December 2009): L1112—L1119. http://dx.doi.org/10.1152/ajplung.00155.2009.
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Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and an important pathogen in patients with chronic lung disease, such as cystic fibrosis and bronchiectasis. The contribution of Toll-like receptor 5 (TLR5) to the innate immune response to this organism is incompletely understood. We exposed wild-type and TLR5-deficient ( Tlr5−/−) mice to aerosolized P. aeruginosa at low and high inocula and assessed bacterial clearance, lung inflammation, and cytokine production 4 and 24 h after infection. Bacterial clearance was impaired in Tlr5−/−mice after low-inoculum, but not high-inoculum, infection. Early bronchoalveolar accumulation of neutrophils was reduced in Tlr5−/−mice after low- and high-dose infection. Cytokine responses, including markedly impaired monocyte chemoattractant protein-1 production 4 h after low- and high-inoculum challenge, were selectively altered in Tlr5−/−mice. In contrast, there was no impairment of bacterial clearance, neutrophil recruitment, or monocyte chemoattractant protein-1 production in Tlr5−/−mice after infection with a nonflagellated isotypic strain of P. aeruginosa . Thus TLR5-mediated recognition of flagellin is involved in activating pulmonary defenses against P. aeruginosa and contributes to antibacterial resistance in a manner that is partially inoculum dependent. These data are the first to demonstrate a unique role for TLR5 in the innate immune response to P. aeruginosa lung infection.
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Reid, Gregor S. D., Kristin Wynne, Kevin She, Darko Curman, Kristy Garbutt, Heather Wildgrove, and Joan Mathers. "Stimulation of Precursor-B Acute Lymphoblastic Leukemia Cells with Toll-Like Receptor Ligands Alters Their Immunogenicity." Blood 104, no. 11 (November 16, 2004): 1887. http://dx.doi.org/10.1182/blood.v104.11.1887.1887.
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Abstract Pediatric pre-B acute lymphoblastic leukemia is the most common childhood cancer. Although current therapies achieve a high rate of remission, relapse of pre-B ALL remains a significant clinical challenge and new forms of therapy are needed. The graft-vs-leukemia (GVL) effect after bone marrow transplantation has shown that the immune system is capable of producing an effective anti-tumor response, which suggests that immune-mediated therapies may provide a complementary treatment strategy. Toll-like receptors (TLR), found on many immune cells, including B cells, have been shown to be important molecules in both innate and adaptive immune responses. Ligation of TLRs with their respective ligands results in an increase in the immunogenicity of antigen presenting cells (APC), through upregulation of MHC antigens and costimulatory molecules and production of cytokines and chemokines. We have previously reported that stimulation of pre-B ALL cells with the TLR9 ligand, CpG DNA, enhances the induction of Th1 immune responses by allogeneic T cells. In this study we examined the expression profile of TLRs 1-8 in precursor-B ALL cells and the effects of TLR ligation on the immune stimulatory capacity of precursor-B ALL cell lines. Eight precursor-B ALL cell lines were used in this study (Nalm6, REH, Sup-B15, KOPN-57bi, 380, 697, OP-1 and RS4:11). Standard RT-PCR analysis was used to examine the expression of TLRs 1-8 by the cell lines. The cell lines were stimulated with ligands for TLR2 (peptidoglycan), TLR3 (poly I:C) and TLR4 (LPS) and evaluated for changes in costimulatory molecule expression and allogeneic T cell stimulation. Non-quantatative PCR detected each TLR, with the exception of TLR8, in the majority of the cell lines. TLR8 was only detected, at low level, in RS4:11 cells. Despite the broad expression profile of the TLRs, significant differences in the effect of TLR ligation were observed between cell lines. In general, only modest increases in CD40 and CD86 expression were observed on responsive cell lines, with the majority of the lines showing no significant changes in response to TLR2, 3 or 4 ligation, despite receptor detection by PCR. Changes in allogeneic T cell proliferation in response to TLR stimulated ALL cell lines were observed, with the largest increases occurring with peptidoglycan and LPS. As was the case with costimulatory molecule expression, no T cell proliferative response change was common to all cell lines. However, analysis of cytokine production by T cells revealed a consistent increase in IFN-gamma and reduction in IL-5 levels in response to peptidoglycan stimulated ALL cells. The results reported in this study indicate that precursor-B ALL cell lines express several TLR molecules and that TLR ligation alters the immunogenicity of the majority of these lines. Interestingly, ligation of TLR2 with peptidoglycan induced a profound shift towards Th1 cytokine production. These observatios suggest that TLR ligation, most notably TLR2 ligation, may provide a strategy to influence anti-ALL immune responses and enhance immune mediated control of this disease.
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Xu, Xun, Yan Nie, Weiwei Wang, Nan Ma, and Andreas Lendlein. "Periodic thermomechanical modulation of toll-like receptor expression and distribution in mesenchymal stromal cells." MRS Communications 11, no. 4 (July 8, 2021): 425–31. http://dx.doi.org/10.1557/s43579-021-00049-5.
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Abstract Toll-like receptor (TLR) can trigger an immune response against virus including SARS-CoV-2. TLR expression/distribution is varying in mesenchymal stromal cells (MSCs) depending on their culture environments. Here, to explore the effect of periodic thermomechanical cues on TLRs, thermally controlled shape-memory polymer sheets with programmable actuation capacity were created. The proportion of MSCs expressing SARS-CoV-2-associated TLRs was increased upon stimulation. The TLR4/7 colocalization was promoted and retained in the endoplasmic reticula. The TLR redistribution was driven by myosin-mediated F-actin assembly. These results highlight the potential of boosting the immunity for combating COVID-19 via thermomechanical preconditioning of MSCs. Graphic abstract Periodic thermal and synchronous mechanical stimuli provided by polymer sheet actuators selectively promoted the expression of SARS-CoV-2-associated TLRs 4 and 7 in adipose-derived MSCs and recruited TLR4 to Endoplasmic reticulum region where TLR7 was located via controlling myosin-mediated F-actin cytoskeleton assembly.
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Frost, Robert A., Gerald J. Nystrom, and Charles H. Lang. "Multiple Toll-like receptor ligands induce an IL-6 transcriptional response in skeletal myocytes." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 3 (March 2006): R773—R784. http://dx.doi.org/10.1152/ajpregu.00490.2005.
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Toll-like receptors (TLRs) comprise a critical sentinel that monitors body compartments for the presence of pathogens. Skeletal muscle expresses TLRs and responds to pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS), by mounting an innate immune response. In the present study, we used C2C12myocytes as a model system for skeletal muscle during infection. C2C12cells responded to LPS in a time frame and with a pattern of gene expression that faithfully mimicked the response of skeletal muscle to LPS in vivo. LPS from a variety of Escherichia coli serotypes stimulated IL-6 synthesis. C2C12cells expressed TLR1–7, but not TLR8 or TLR9, mRNA by RT-PCR. A synthetic tripalmitoylated cysteine-, serine-, and lysine-containing peptide (Pam) and LPS from Porphyromonas gingivalis, two TLR2 ligands, also stimulated IL-6 expression. LPS and Pam stimulated luciferase activity driven from NF-κB and IL-6 promoter-containing plasmids, and this response was blunted when the NF-κB binding site was mutated. LPS- and Pam-stimulated IL-6 expression was inhibited by the proteasome inhibitor MG-132 and the IκB kinase-2 (IKK2) inhibitor 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1). Pam-stimulated NF-κB and IL-6 promoter activities were disrupted by a dominant-negative form of TLR2, but not TLR4. Local injection of LPS or Pam into the gastrocnemius muscle stimulated IL-6 mRNA expression in the injected, but not the contralateral, muscle. The LPS- but not Pam-stimulated expression of IL-6 mRNA was blunted in skeletal muscle of mice carrying an inactivating mutation in TLR4. The data suggest that skeletal muscle and muscle cells recognize pathogen-associated molecules with specific TLRs to initiate an IL-6 transcriptional response.
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Khan, Imran, Emanuel Maldonado, Liliana Silva, Daniela Almeida, Warren E. Johnson, Stephen J. O’Brien, Guojie Zhang, Erich D. Jarvis, M. Thomas P. Gilbert, and Agostinho Antunes. "The Vertebrate TLR Supergene Family Evolved Dynamically by Gene Gain/Loss and Positive Selection Revealing a Host–Pathogen Arms Race in Birds." Diversity 11, no. 8 (August 12, 2019): 131. http://dx.doi.org/10.3390/d11080131.
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The vertebrate toll-like receptor (TLRs) supergene family is a first-line immune defense against viral and non-viral pathogens. Here, comparative evolutionary-genomics of 79 vertebrate species (8 mammals, 48 birds, 11 reptiles, 1 amphibian, and 11 fishes) revealed differential gain/loss of 26 TLRs, including 6 (TLR3, TLR7, TLR8, TLR14, TLR21, and TLR22) that originated early in vertebrate evolution before the diversification of Agnatha and Gnathostomata. Subsequent dynamic gene gain/loss led to lineage-specific diversification with TLR repertoires ranging from 8 subfamilies in birds to 20 in fishes. Lineage-specific loss of TLR8-9 and TLR13 in birds and gains of TLR6 and TLR10-12 in mammals and TLR19-20 and TLR23-27 in fishes. Among avian species, 5–10% of the sites were under positive selection (PS) (omega 1.5–2.5) with radical amino-acid changes likely affecting TLR structure/functionality. In non-viral TLR4 the 20 PS sites (posterior probability PP > 0.99) likely increased ability to cope with diversified ligands (e.g., lipopolysaccharide and lipoteichoic). For viral TLR7, 23 PS sites (PP > 0.99) possibly improved recognition of highly variable viral ssRNAs. Rapid evolution of the TLR supergene family reflects the host–pathogen arms race and the coevolution of ligands/receptors, which follows the premise that birds have been important vectors of zoonotic pathogens and reservoirs for viruses.
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Kato, Kosuke, Wenju Lu, Hirofumi Kai, and K. Chul Kim. "Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 3 (September 2007): L686—L692. http://dx.doi.org/10.1152/ajplung.00423.2006.
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MUC1 is a membrane-tethered mucin-like glycoprotein expressed on the surface of various mucosal epithelial cells as well as hematopoietic cells. Recently, we showed that MUC1 suppresses flagellin-induced Toll-like receptor (TLR) 5 signaling both in vivo and in vitro through cross talk with TLR5. In this study, we determined whether phosphoinositide 3-kinase (PI3K), a negative regulator of TLR5 signaling, is involved in the cross talk between MUC1 and TLR5 using various genetically modified epithelial cell lines. Our results showed 1) activation of MUC1 induced recruitment of the PI3K regulatory subunit p85 to the MUC1 cytoplasmic tail (CT) as well as Akt phosphorylation, 2) MUC1-induced Akt phosphorylation required the presence of Tyr20 within the PI3K binding motif of the MUC1 CT, and 3) mutation of Tyr20 or pharmacological inhibition of PI3K activation failed to block MUC1-induced suppression of TLR5 signaling. We conclude that whereas PI3K is downstream of MUC1 activation and negatively regulates TLR5 signaling, it is not responsible for MUC1-induced suppression of TLR5 signaling.
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Thomas, Amy, Carl Laxton, Joanne Rodman, Nisha Myangar, Nigel Horscroft, and Tanya Parkinson. "Investigating Toll-Like Receptor Agonists for Potential To Treat Hepatitis C Virus Infection." Antimicrobial Agents and Chemotherapy 51, no. 8 (June 4, 2007): 2969–78. http://dx.doi.org/10.1128/aac.00268-07.
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ABSTRACT Toll-like receptors (TLRs) are key mediators of innate immunity, and their activation by microbial components leads to the production of cytokines and interferons. Recombinant alpha interferon has been used to treat several viral diseases and is the current standard of care for hepatitis C virus (HCV) infection. Recently, agonists of TLR7 and TLR9 have been shown to have clinical efficacy in HCV patients, and this is correlated with their ability to induce endogenous type I interferon production. We have carried out a comprehensive study of agonists of TLRs 1 to 9 to determine if any additional TLRs can induce antiviral molecules from human peripheral blood mononuclear cells (PBMCs). The agonists were incubated with PBMCs, and the supernatant was then removed and added to HCV replicon cells to assess antiviral activity. Agonists of TLRs 3, 4, 7, 8, and 9 were found to be potent inducers of antiviral activity in PBMC supernatants, and the activity correlated with the induction of alpha interferon and the interferon-induced antiviral biomarker 2′,5′-oligoadenylate synthase. Antiviral activity of TLR7 and TLR8 agonists was blocked by an antibody that binds to the type I interferon receptor, confirming that the antiviral activity results from type I interferon induction. TLR4 and TLR8 agonists were found to strongly induce the proinflammatory cytokines interleukin 1β and tumor necrosis factor alpha at concentrations similar to those inducing antiviral activity. This raises concerns about adverse side effects if these were to be used as antiviral agents. We therefore conclude that TLRs 3, 7, and 9 represent the most attractive targets for the development of new HCV therapies.
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Parapanov, Roumen, Jérôme Lugrin, Nathalie Rosenblatt-Velin, François Feihl, Bernard Waeber, Giuseppina Milano, Catherine Vergely, Na Li, Pal Pacher, and Lucas Liaudet. "Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischaemia-reperfusion in the mouse." Clinical Science 129, no. 2 (April 30, 2015): 187–98. http://dx.doi.org/10.1042/cs20140444.
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In the present study, we report that genetic deletion of toll-like receptor 5 (TLR5) is associated with increased myocardial injury and dysfunction following ischaemia-reperfusion, by enhancing cardiac oxidative stress and p38 activation. TLR5 may thus convey cardioprotective signals during myocardial infarction (MI).
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Iqbal, Muhammad, Victoria J. Philbin, G. S. K. Withanage, Paul Wigley, Richard K. Beal, Marianne J. Goodchild, Paul Barrow, et al. "Identification and Functional Characterization of Chicken Toll-Like Receptor 5 Reveals a Fundamental Role in the Biology of Infection with Salmonella enterica Serovar Typhimurium." Infection and Immunity 73, no. 4 (April 2005): 2344–50. http://dx.doi.org/10.1128/iai.73.4.2344-2350.2005.
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ABSTRACT Toll-like receptors (TLRs) are a major component of the pattern recognition receptor repertoire that detect invading microorganisms and direct the vertebrate immune system to eliminate infection. In chickens, the differential biology of Salmonella serovars (systemic versus gut-restricted localization) correlates with the presence or absence of flagella, a known TLR5 agonist. Chicken TLR5 (chTLR5) exhibits conserved sequence and structural similarity with mammalian TLR5 and is expressed in tissues and cell populations of immunological and stromal origin. Exposure of chTLR5+ cells to flagellin induced elevated levels of chicken interleukin-1β (chIL-1β) but little upregulation of chIL-6 mRNA. Consistent with the flagellin-TLR5 hypothesis, an aflagellar Salmonella enterica serovar Typhimurium fliM mutant exhibited an enhanced ability to establish systemic infection. During the early stages of infection, the fliM mutant induced less IL-1β mRNA and polymorphonuclear cell infiltration of the gut. Collectively, the data represent the identification and functional characterization of a nonmammalian TLR5 and indicate a role in restricting the entry of flagellated Salmonella into systemic sites of the chicken.
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Sun, Jun, Pamela E. Fegan, Anjali S. Desai, James L. Madara, and Michael E. Hobert. "Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 3 (March 2007): G767—G778. http://dx.doi.org/10.1152/ajpgi.00447.2006.
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Salmonella typhimurium is a gram-negative enteric pathogen that invades the mucosal epithelium and is associated with diarrheal illness in humans. Flagellin from S. typhimurium and other gram-negative bacteria has been shown to be the predominant proinflammatory mediator through activation of the basolateral Toll-like receptor 5 (TLR5). Recent evidence has shown that prior exposure can render immune cells tolerant to subsequent challenges by TLR ligands. Accordingly, we examined whether prior exposure to purified flagellin would render human intestinal epithelial cells insensitive to future contact. We found that flagellin-induced tolerance is common to polarized epithelial cells and prevents further activation of proinflammatory signaling cascades by both purified flagellin and Salmonella bacteria but does not affect TNF-α stimulation of the same pathways. Flagellin tolerance is a rapid process that does not require protein synthesis, and that occurs within 1 to 2 h of flagellin exposure. Prolonged flagellin exposure blocks activation of the NF-κB, MAPK, and phosphoinositol 3-kinase signaling pathways and results in the internalization of a fraction of the basolateral TLR5 without affecting the polarity or total expression of TLR5. After removal of flagellin, cells require more than 24 h to fully recover their ability to mount a normal proinflammatory response. We have found that activation of phosphoinositol 3-kinase and Akt by flagellin has a small damping effect in the early stages of flagellin signaling but is not responsible for tolerance. Our study indicates that inhibition of TLR5-associated IL-1 receptor-associated kinase-4 activity occurs during the development of flagellin tolerance and is likely to be the cause of tolerance.
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Taylor, Tammi, Wilbert Derbigny, Young-June Kim, and Hal E. Broxmeyer. "Expression of Functional Toll-Like Receptor 2 on Mouse Embryonic Stem Cells." Blood 112, no. 11 (November 16, 2008): 4746. http://dx.doi.org/10.1182/blood.v112.11.4746.4746.
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Abstract Embryonic stem (ES) cells have the capacity to produce all cell types of the body. Understanding murine ES (mES) cell proliferation, survival, differentiation, and self renewal will enhance knowledge of developmental biology and essential use of ES cells. Recently, Toll Like Receptor (TLR) activation has been shown by others to play a role in influencing the differentiation of hematopoietic stem cells. Previous studies have also shown that TLR activation prevents mesenchymal stem cell differentiation into adipocytes, chondrocytes, and osteocytes and plays a role in bone repair. We hypothesized that certain TLR’s would be expressed on mES cells and that the ligands for these expressed TLR’s would induce functional activity in the mESC’s. Therefore, we wanted to determine if TLRs are expressed on mES cells and if so, are they functional. Three different mES cell lines (R1, CGR8, and E14) were used to determine if TLRs are expressed at the mRNA level using primers for murine TLR1-9 mRNA. We found that TLR’s 1, 2, 3, 6, and 9 were expressed at the mRNA level, but TLR’s 4, 5, 7, and 8 were not. Based on the availability of antibodies to TLR’s, and using flow cytometry, we found expression of TLR2 but not TLR 4 on the surface of all three mES cell lines. TLR ligands were used to treat mES cells in the presence of leukemia inhibitory factor (LIF) for an hour. Activation of TLR2 by its ligand Pam3Cys, a synthetic tri-acyl lipoprotein, on mES cells induced NF-κβ nuclear translocation when compared to ES cells not stimulated with TLR ligands. LPS, the ligand for TLR4 did not induce NF-κβ nuclear translocation on ES cells, consistent with lack of cell surface expression of TLR4 on mES cells. TLR expression and TLR ligand interaction were not associated with changes in the morphology of the mES cells or expression of Oct-4, SSEA-1, KLF-4, or Sox-2, markers for maintenance of the undifferentiated state of mES cells. This suggests that the cells remain in an undifferentiated state even after TLR activation by Pam3Cys in the presence of LIF. Thus our study has identified functionally active TLR2 on the surface of mES cells, information that may be of use to further defining a role for TLR’s on ES cells, and for manipulation of other ES cell functions.
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Chang, Ching, Hung-Kai Liu, Chao-Bin Yeh, Ming-Lin Yang, Wen-Chieh Liao, Chiung-Hui Liu, and To-Jung Tseng. "Cross-Talk of Toll-Like Receptor 5 and Mu-Opioid Receptor Attenuates Chronic Constriction Injury-Induced Mechanical Hyperalgesia through a Protein Kinase C Alpha-Dependent Signaling." International Journal of Molecular Sciences 22, no. 4 (February 14, 2021): 1891. http://dx.doi.org/10.3390/ijms22041891.
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Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) in Sprague-Dawley rats, which were assigned into CCI and Decompression groups randomly. In Decompression group, the rats were performed with nerve decompression at post-operative week 4. Mechanical hyperalgesia and mechanical allodynia were obviously attenuated after a month. Toll-like receptor 5 (TLR5)-immunoreactive (ir) expression increased in dorsal horn, particularly in the inner part of lamina II. Additionally, substance P (SP) and isolectin B4 (IB4)-ir expressions, rather than calcitonin-gene-related peptide (CGRP)-ir expression, increased in their distinct laminae. Double immunofluorescence proved that increased TLR5-ir expression was co-expressed mainly with IB4-ir expression. Through an intrathecal administration with FLA-ST Ultrapure (a TLR5 agonist, purified flagellin from Salmonella Typhimurium, only the CCI-induced mechanical hyperalgesia was attenuated dose-dependently. Moreover, we confirmed that mu-opioid receptor (MOR) and phospho-protein kinase Cα (pPKCα)-ir expressions but not phospho-protein kinase A RII (pPKA RII)-ir expression, increased in lamina II, where they mostly co-expressed with IB4-ir expression. Go 6976, a potent protein kinase C inhibitor, effectively reversed the FLA-ST Ultrapure- or DAMGO-mediated attenuated trend towards mechanical hyperalgesia by an intrathecal administration in CCI rats. In summary, our current findings suggest that nerve decompression improves CCI-induced mechanical hyperalgesia that might be through the cross-talk of TLR5 and MOR in a PKCα-dependent manner, which opens a novel opportunity for the development of analgesic therapeutics in neuropathic pain.
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Hoang, Thi Xoan, Cao Nguyen Duong, and Jae Young Kim. "Identification and Characterization of a Splicing Variant in the 5′ UTR of the Human TLR5 Gene." BioMed Research International 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/8727434.
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Toll-like receptors (TLRs) are essential components of the innate immune system. TLR5 is the receptor for flagellin, the principal protein component of bacterial flagella. The TLR5 gene has 6 exons. In an RT-PCR analysis, we found long TLR5 transcripts, in addition to those of the expected size (short TLR5 transcripts). A sequence analysis revealed that the long TLR5 transcripts contain a new exon of 94 nucleotides located between previously reported exons IV and V in the 5′ untranslated region (5′ UTR). A real-time PCR analysis of the two alternatively spliced variants in various cell lines showed that the long TLR5 transcripts are abundantly expressed in nonimmune cells. The ratios of long/short transcripts in human nonimmune cell lines, such as A549, T98G, HaCaT, H460, HEK-293, and Caco-2 cells, and primary mesenchymal stem cells were in the range of 1.25 to 4.31. In contrast, those of human monocytic THP-1 and U937 cells and E6.1 T cells and Ramos B cells were around 0.9. These ratios in human monocytic THP-1 cells were decreased by treatment with IFN-γ in a concentration-dependent manner. Based on our findings, we suggest that the newly found long TLR5 transcripts may be involved in the negative regulation of TLR5 expression and function.
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Moreno, María, Berber M. Mol, Silvia von Mensdorff-Pouilly, René HM Verheijen, Esther C. de Jong, B. Mary E. von Blomberg, Alfons JM van den Eertwegh, Rik J. Scheper, and Hetty J. Bontkes. "Differential indirect activation of human invariant natural killer T cells by Toll-like receptor agonists." Immunotherapy 1, no. 4 (July 2009): 557–70. http://dx.doi.org/10.2217/imt.09.30.
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Aim: Invariant natural killer (iNK) T cells are activated by bacterial glycosphingolipids presented by CD1d on dendritic cells (DCs). Here, it was investigated whether Toll-like receptor (TLR) ligands derived from various microorganisms can either directly or indirectly (through DC activation) activate iNKT cells. Materials & Methods: TLR expression by iNKT cells was examined and the ability of various TLR ligands to activate iNKT cells was evaluated. Results: Although human iNKT cells express all TLRs, apart from TLR8, they did not respond directly to TLR ligands. However, iNKT cells became strongly activated when total peripheral blood mononuclear cells were stimulated with TLR2/6, 7/8 and 9 ligands, but not or to a lesser extent with TLR3, 4 and 5 ligands. TLR-stimulated monocyte-derived DCs promoted iNKT cell phenotypic activation and, in turn, these activated iNKT cells further enhanced DC maturation. Conclusion: TLR agonists may act as strong adjuvants for immunotherapy by promoting combined and reciprocal activation of iNKT cells and DCs.
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Root-Bernstein, Robert. "Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions." International Journal of Molecular Sciences 22, no. 4 (February 20, 2021): 2108. http://dx.doi.org/10.3390/ijms22042108.
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Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.
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Rout, Ajaya Kumar, Varsha Acharya, Diptimayee Maharana, Budheswar Dehury, Sheela Rani Udgata, Rajkumar Jena, Bhaskar Behera, Pranaya Kumar Parida, and Bijay Kumar Behera. "Insights into structure and dynamics of extracellular domain of Toll-like receptor 5 in Cirrhinus mrigala (mrigala): A molecular dynamics simulation approach." PLOS ONE 16, no. 1 (January 14, 2021): e0245358. http://dx.doi.org/10.1371/journal.pone.0245358.
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The toll-like receptor 5 (TLR5) is the most conserved important pattern recognition receptors (PRRs) often stimulated by bacterial flagellins and plays a major role in the first-line defense against invading pathogenic bacteria and in immune homeostasis. Experimental crystallographic studies have shown that the extracellular domain (ECD) of TLR5 recognizes flagellin of bacteria and functions as a homodimer in model organism zebrafish. However, no structural information is available on TLR5 functionality in the major carp Cirrhinus mrigala (mrigala) and its interaction with bacterial flagellins. Therefore, the present study was undertaken to unravel the structural basis of TLR5-flagellin recognition in mrigala using structural homodimeric TLR5-flagellin complex of zebrafish as reference. Integrative structural modeling and molecular dynamics simulations were employed to explore the structural and mechanistic details of TLR5 recognition. Results from structural snapshots of MD simulation revealed that TLR5 consistently formed close interactions with the three helices of the D1 domain in flagellin on its lateral side mediated by several conserved amino acids. Results from the intermolecular contact analysis perfectly substantiate with the findings of per residue-free energy decomposition analysis. The differential recognition mediated by flagellin to TLR5 in mrigala involves charged residues at the interface of binding as compared to the zebrafish complex. Overall our results shows TLR5 of mrigala involved in innate immunity specifically recognized a conserved site on flagellin which advocates the scientific community to explore host-specific differences in receptor activation.
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Vijay-Kumar, Matam, Jesse D. Aitken, Amrita Kumar, Andrew S. Neish, Satoshi Uematsu, Shizuo Akira, and Andrew T. Gewirtz. "Toll-Like Receptor 5-Deficient Mice Have Dysregulated Intestinal Gene Expression and Nonspecific Resistance to Salmonella-Induced Typhoid-Like Disease." Infection and Immunity 76, no. 3 (January 14, 2008): 1276–81. http://dx.doi.org/10.1128/iai.01491-07.
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ABSTRACT The recognition of flagellin by Toll-like receptor 5 (TLR5) is the dominant means by which model intestinal epithelia activate proinflammatory gene expression in response to Salmonella enterica. The role of the flagellin-TLR5 interaction in vivo has been addressed primarily via studies that use flagellar mutants. Such studies suggest that host recognition of flagellin promotes rapid neutrophil recruitment that protects the host from this pathogen. However, these works do not directly address the role of TLR5 and are subject to the caveat that flagellar mutations may broadly affect Salmonella gene expression. Thus, we examined the role of the flagellin-TLR5 interaction via the use of TLR5-deficient (TLR5KO) mice. We utilized both the traditional model of murine Salmonella infection, wherein low-dose oral infection of mice with Salmonella enterica subsp. enterica serovar Typhimurium results in systemic typhoid-like disease, and a more recently characterized model in which mice are pretreated with streptomycin to result in gut-restricted acute enteritis. In the enteritis model, TLR5KO mice had more severe gut pathology, thus “phenocopying” previous results obtained with Salmonella mutants. In contrast, TLR5KO mice were resistant to Salmonella-induced typhoid-like disease. However, such resistance was not specific for flagellated serovar Typhimurium, but rather, TLR5KO mice were also resistant to challenges by flagellin-deficient serovar Typhimurium. Such resistance associated with elevations in the microbiota was ablated by antibiotic pretreatment and correlated with basal elevations in intestinal host defense gene expression. All together, these results indicate that the resistance of TLR5KO mice to Salmonella-induced typhoid-like illness resulted from alterations in their basal phenotype rather than from the lack of TLR5 ligation during the infection per se.
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Beilmann-Lehtonen, Ines, Jaana Hagström, Harri Mustonen, Selja Koskensalo, Caj Haglund, and Camilla Böckelman. "High Tissue TLR5 Expression Predicts Better Outcomes in Colorectal Cancer Patients." Oncology 99, no. 9 (2021): 589–600. http://dx.doi.org/10.1159/000516543.
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<b><i>Background:</i></b> Colorectal cancer (CRC), the third most common cancer globally, caused 881,000 cancer deaths in 2018. Toll-like receptors (TLRs), the primary sensors of pathogen-associated molecular patterns and damage-associated molecular patterns, activate innate and adaptive immune systems and participate in the development of an inflammatory tumor microenvironment. We aimed to explore the prognostic value of TLR3, TLR5, TLR7, and TLR9 tissue expressions in CRC patients. <b><i>Methods:</i></b> Using immunohistochemistry, we analyzed tissue microarray samples from 825 CRC patients who underwent surgery between 1982 and 2002 at the Department of Surgery, Helsinki University Hospital, Finland. After analyzing a pilot series of 205 tissue samples, we included only TLR5 and TLR7 in the remainder of the patient series. We evaluated the associations between TLR5 and TLR7 tissue expressions, clinicopathologic variables, and survival. Using the Kaplan-Meier method, we generated survival curves, determining significance using the log-rank test. Univariate and multivariate survival analyses relied on the Cox proportional hazards model. <b><i>Results:</i></b> The 5-year disease-specific survival was 55.9% among TLR5-negative (95% confidence interval [CI] 50.6–61.2%) and 61.9% (95% CI 56.6–67.2%; <i>p</i> = 0.011, log-rank test) among TLR5-positive patients. In the Cox multivariate survival analysis adjusted for age, sex, stage, location, and grade, positive TLR5 immunoexpression (hazard ratio [HR] 0.74; 95% CI 0.59–0.92; <i>p</i> = 0.007) served as an independent positive prognostic factor. TLR7 immunoexpression exhibited no prognostic value in the survival analysis across the entire cohort (HR 0.97; 95% CI 0.78–1.20; <i>p</i> = 0.754) nor in subgroup analyses. <b><i>Conclusions:</i></b> We show for the first time that a high TLR5 tumor tissue expression associates with a better prognosis in CRC patients.
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Hershberg, Robert M. "V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 4 (October 1, 2002): G833—G839. http://dx.doi.org/10.1152/ajpgi.00208.2002.
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The intestinal epithelial cell (IEC) is exposed at the apical surface to a high concentration of foreign antigen and bacterial products capable of triggering inflammatory responses. Complex intracellular pathways of antigen trafficking and the polarized expression of immunologically active receptors provide additional means to regulate the inflammatory pathways in these cells. In the case of human leukocyte antigen (HLA) class II heterodimers, surface expression is highly restricted to the basolateral surface, and this also appears to be the case for Toll-like receptor 5 (TLR5) on polarized T84 human colon cancer cells. Processing of soluble antigen via HLA class II in IEC can occur following internalization from the apical surface but is highly inefficient. In addition, certain bacteria can facilitate the transport of flagellin (the ligand for TLR5) across an intact epithelium. Disruption of the tight junctions between IECs, allowing direct access of antigen and flagellin to the basolateral surface of the cell, dramatically affects the functional outcome HLA class II and TLR5 pathways.
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Yu, Xiaoqin, Ran Chen, Fei Wang, Weihua Liu, Wenjing Zhang, Maolei Gong, Han Wu, et al. "Pattern recognition receptor-initiated innate immune responses in mouse prostatic epithelial cells." Biology of Reproduction 105, no. 1 (April 23, 2021): 113–27. http://dx.doi.org/10.1093/biolre/ioab076.
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Abstract Three major pathogenic states of the prostate, including benign prostatic hyperplasia, prostate cancer, and prostatitis, are related to the local inflammation. However, the mechanisms underlying the initiation of prostate inflammation remain largely unknown. Given that the innate immune responses of the tissue-specific cells to microbial infection or autoantigens contribute to local inflammation, this study focused on pattern recognition receptor (PRR)-initiated innate immune responses in mouse prostatic epithelial cells (PECs). Primary mouse PECs abundantly expressed Toll-like receptor 3 (TLR3), TLR4, TLR5, melanoma differentiation-associated protein 5 (MDA5), and IFN-inducible protein 16 (p204 in mouse). These PRRs can be activated by their respective ligands: lipopolysaccharide (LPS) and flagellin of Gram-negative bacteria for TLR4 and TLR5, polyinosinic-polycytidylic acid (poly(I:C)) for TLR3 and MDA5, and herpes simplex virus DNA analog (HSV60) for p204. LPS and flagellin predominantly induced the expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFA), interleukin 6 (IL6), chemokines monocyte chemoattractant protein-1 (MCP1), and C-X-C motif chemokine 10 (CXCL10). Poly(I:C) and HSV60 predominantly induced the expression of type 1 interferons (IFNA and IFNB) and antiviral proteins: Mx GTPase 1, 2′,5′-oligoadenylate synthetase 1, and IFN-stimulated gene 15. The replication of mumps virus in PECs was inhibited by type 1 IFN signaling. These findings provide insights into the mechanisms underlying innate immune response in the prostate.
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Chen, Jie, Jaladanki N. Rao, Tongtong Zou, Lan Liu, Bernard S. Marasa, Lan Xiao, Xing Zeng, Douglas J. Turner, and Jian-Ying Wang. "Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 3 (September 2007): G568—G576. http://dx.doi.org/10.1152/ajpgi.00201.2007.
Full textAbstract:
The Toll-like receptors (TLRs) allow mammalian intestinal epithelium to detect various microbes and activate innate immunity after infection. TLR2 and TLR4 have been identified in intestinal epithelial cells (IECs) as fundamental components of the innate immune response to bacterial pathogens, but the exact mechanism involved in control of TLR expression remains unclear. Polyamines are implicated in a wide variety of biological functions, and regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions. The current study determined whether polyamines regulate TLR expression, thereby modulating intestinal epithelial barrier function. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine decreased levels of TLR2 mRNA and protein, whereas increased polyamines by ectopic overexpression of the ODC gene enhanced TLR2 expression. Neither intervention changed basal levels of TLR4. Exposure of normal IECs to low-dose (5 μg/ml) LPS increased ODC enzyme activity and stimulated expression of TLR2 but not TLR4, while polyamine depletion prevented this LPS-induced TLR2 expression. Decreased TLR2 in polyamine-deficient cells was associated with epithelial barrier dysfunction. In contrast, increased TLR2 by the low dose of LPS enhanced epithelial barrier function, which was abolished by inhibition of TLR2 expression with specific, small interfering RNA. These results indicate that polyamines are necessary for TLR2 expression and that polyamine-induced TLR2 activation plays an important role in regulating epithelial barrier function.
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Kwon, Ji Hye, Miyeon Kim, Soyoun Um, Hyang Ju Lee, Yun Kyung Bae, Soo Jin Choi, Hyun Ho Hwang, Wonil Oh, and Hye Jin Jin. "Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling." Cells 10, no. 1 (January 3, 2021): 63. http://dx.doi.org/10.3390/cells10010063.
Full textAbstract:
In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.
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Jing, Xu, Chen Min, Liu Qi Yun, Hu Shun Qin, Li Li Rui, Li Jia, and Ma Run Mei. "Toll-like receptor 2/4 inhibitors can reduce preterm birth in mice." Journal of International Medical Research 48, no. 10 (October 2020): 030006052093379. http://dx.doi.org/10.1177/0300060520933795.
Full textAbstract:
Objectives Preterm birth (PTB) occurs in 5% to 18% of newborns. However, the underlying inflammatory mechanisms have not been elucidated. Methods We established a mouse model of infection-associated PTB. Physical signs in pregnant mice with or without lipopolysaccharide (LPS) treatment were observed, and the frequencies of Toll-like receptor (TLR)2- and TLR4-positive CD11b+ cells were analyzed. Cytokine levels in plasma and pathological changes were assessed following LPS treatment. A rescue experiment was used to probe potential immunologic mechanisms underlying PTB. Results Lymphocyte infiltration could be observed in the placentas of mice following intrauterine injection with LPS. The percentage of inflammatory cells decreased 12 hours after treatment. Moreover, TLR2 and TLR4 expression in peripheral blood cells was significantly increased 4 hours after intraperitoneal injection of LPS. Peak TLR2 and TLR4 expression in peripheral blood cells occurred 8 hours post-treatment. TLR4 and TLR-2/4 inhibitors reduced levels of interleukin-10, interferon-γ, and tumor necrosis factor-α in peripheral blood and delayed PTB. Conclusions TLR2 and TLR4 inhibition could play important roles in PTB.