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Literatura académica sobre el tema "Toll-like receptor 5 (TLR5)"

Autor: Grafiati

Publicado: 4 de junio de 2021

Última modificación: 16 de febrero de 2022

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Artículos de revistas sobre el tema "Toll-like receptor 5 (TLR5)"

Zhang, Zhe, Jean-Pierre Louboutin, Daniel J. Weiner, Joanna B. Goldberg y James M. Wilson. "Human Airway Epithelial Cells Sense Pseudomonas aeruginosa Infection via Recognition of Flagellin by Toll-Like Receptor 5". Infection and Immunity 73, n.º 11 (noviembre de 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 y Marc E. Rothenberg. "Toll-Like Receptor Signaling Inhibits Eosinophilopoiesis." Blood 116, n.º 21 (19 de noviembre de 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 y Sandra Sacre. "TLR1/2 and 5 induce elevated cytokine levels from rheumatoid arthritis monocytes independent of ACPA or RF autoantibody status". Rheumatology 59, n.º 11 (28 de junio de 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 y Lucile Baseggio. "Toll-Like Receptor Profiles In Splenic Marginal Zone B-Cell Lymphoma and Splenic Diffuse Red Pulp B-Cell Lymphoma". Blood 122, n.º 21 (15 de noviembre de 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 y 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, n.º 3 (septiembre de 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, n.º 21 (18 de noviembre de 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 y 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, n.º 3 (marzo de 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 y 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 y Jan A. M. van Laar. "Leukocyte toll-like receptor expression in pathergy positive and negative Behçet’s disease patients". Rheumatology 59, n.º 12 (5 de agosto de 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 y Alan Aderem. "A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin". Journal of Experimental Medicine 204, n.º 2 (5 de febrero de 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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Tesis sobre el tema "Toll-like receptor 5 (TLR5)"

Angers, Isabelle. "Validation of the candidacy of toll-like receptor 5 (Tlr5) as a Salmonella susceptibility gene". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=81587.

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The extreme susceptibility to infection with Salmonella Typhimurium of wild-derived MOLF/Ei has been linked to one chromosomal region (Ity3). Toll-like receptor 5 (Tlr5) is located within the Ity3 interval and its candidacy as a Salmonella-susceptibility gene was evaluated in vitro and in vivo by comparing the Tlr5 C57BL/6J and MOLF/Ei alleles (85). In vitro studies using NF-kappaB-dependent reporter genes showed that sequence variants found within the coding region of MOLF/Ei Tlr5 did not affect the response of Tlr5 to flagellin compared to C57BL/6J. MOLF/Ei promoter had a slightly stronger basal activity than the C57BL/6J allele. In vivo study using Ity3 congenic mice showed that mice homozygous for MOLF/Ei allele at Ity3 had a stronger response to flagellin as measured by IL-6 secretion in the serum. Finally, we can conclude that Tlr5 is involved in the disease phenotype underlying Ity3 however, it is not clear if the impact of Tlr5 is primary or secondary.

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Porte, Rémi. "Caractérisation des propriétés anti-infectieuses de la flagelline, agoniste du Toll-like receptor 5". Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S065/document.

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De par sa capacité à détecter les microorganismes et à mettre en place une défense anti-infectieuse rapide, l’immunité innée représente la première ligne de défense de l’hôte. La réponse immunitaire innée est déclenchée par des motifs microbiens moléculaires universels et conservés reconnus par des récepteurs innés parmi lesquels les "Toll-like Receptors" (TLR). L’activation de ces récepteurs induit une inflammation locale et une réponse antimicrobienne adaptée au pathogène. Ces propriétés biologiques ont permis de d’envisager l’utilisation des TLR comme cible thérapeutique antiinfectieuse. Dans ce contexte il a été montré que la flagelline, le composant majeur des flagelles bactériens et le seul agoniste de TLR5 décrit à ce jour, possédait des propriétés anti-infectieuses. Des études chez la souris ont montré que la flagelline induisait une forte production, par des cellules lymphoïdes innées, d’IL-22, une cytokine impliquées dans la protection des muqueuses. Par ailleurs, la forte expression de TLR5 par les cellules épithéliales laisse présager un rôle de ces cellules dans les propriétés anti-infectieuses de la flagelline. Toutefois, les mécanismes moléculaires et cellulaires effecteurs responsables des effets antimicrobiens de l’agoniste de TLR5 restent à définir.Au cours de ce travail de thèse, nous avons étudié les capacités anti-infectieuses de la flagelline dans deux modèles infectieux chez la souris. Nous avons tout d’abord montré que l’administration systémique de flagelline, en prophylaxie c’est-à-dire préalablement au challenge infectieux, permettait de protéger d’une infection intestinale par Yersinia pseudotuberculosis. La protection induite par la flagelline est observable lors d’une infection par la voie muqueuse mais est absente lors d’un challenge infectieux par la voie systémique, démontrant ainsi le caractère muqueux de la protection. L’effet protecteur de la flagelline dans notre modèle est dépendant de l’expression de TLR5 et indépendant de l’IL-22. Cette étude suggère donc un mécanisme original de protection médié par la flagelline, indépendant de l’IL-22.Nous avons également analysé la capacité anti-infectieuse de la flagelline dans un modèle murin d’infection respiratoire à Streptococcus pneumoniae. Nous avons notamment montré que la flagelline pouvait être utilisée en thérapeutique lorsqu’elle était associée à un antibiotique. En effet, l’association d’amoxicilline ou de co-trimoxazole avec la flagelline (voie intranasale) a permis de protéger des souris infectées par une dose létale de S. pneumoniae comparativement à l’antibiotique seul. L’efficacité de cette thérapie est dépendante de l’activation de TLR5 et est associée à une infiltration pulmonaire importante de polynucléaires neutrophiles. Ce traitement combinatoire améliore également la protection dans un modèle de surinfection pneumococcique post-grippale. Ces résultats montrent que la combinaison agoniste de TLR5/antibiotique améliore la réponse anti-infectieuse pulmonaire et permettent d’envisager de nouvelles stratégies antibactériennes dans le cas d’infections où les antibiotiques montrent leurs limites (infections nosocomiales, bactéries multirésistantes…)
With its ability to sense micro-organisms and to induce a rapid defense against infections, innate immunity represents the first line of host’s defense. The innate immune response is triggered by universal and conserved microbial molecular patterns recognized by innate receptors including the Toll-like receptors (TLRs). Activation of these receptors induces local inflammation and antimicrobial response against pathogens. These biological properties have allowed considering the use of TLR as anti-infective therapeutic target. In this context it has been shown that flagellin, the major component of bacterial flagella and the agonist of TLR5, had anti-infectious properties. It was shown that flagellin induces a strong production by innate lymphoid cells of IL-22, a cytokine involved in the protection of mucosa. Furthermore, the strong expression of TLR5 by epithelial cells suggests a role for these cells in the anti-infectious properties of flagellin. However, the molecular and cellular mechanisms responsible for the antimicrobial effects of the TLR5 agonist remained to be defined.In this thesis, we studied the anti-infectious properties of flagellin in two infectious murine models. We first showed that systemic administration of flagellin, prior to infectious challenge, protect against an intestinal infection with Yersinia pseudotuberculosis. The protection induced by flagellin is observable upon infection by mucosal route but is absent during a challenge by the systemic route, thus demonstrating the role of the mucosa for the protection. The anti-bacterial effect in this model is dependent on the expression of TLR5 and independent of the innate lymphoid cells’ IL-22 production. This study suggests a novel mechanism of flagellin-mediated protection, independent of the IL-22.We also analyzed the anti-infectious abilities of flagellin in a murine model of respiratory infection by Streptococcus pneumoniae. In particular, we showed that flagellin could be used in therapy when combined to an antibiotic. Indeed, the combination of amoxicillin or co-trimoxazole with flagellin protected mice infected with a lethal dose of S. pneumoniae compared to antibiotic standalone. The effectiveness of this therapy was dependent on the activation of TLR5 and was associated with pulmonary infiltration of neutrophils. This combinatory treatment also improved the protection in a model of post-influenza pneumococcal superinfection. These results show that the combination of TLR5 agonist / antibiotic ameliorates pulmonary anti-infectious response and allow to consider new antibacterial strategies against infections when antibiotics reach their limits (nosocomial infections, multiresistant bacteria ...)

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Moretti, Isabele Fattori. "Receptor do tipo Toll 4 dentre os TLRs de membrana plasmática possui um papel na malignidade de astrocitomas". Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-05122018-131346/.

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Os receptores do tipo Toll (TLRs) são as primeiras proteínas do sistema imune a identificarem distúrbios, reconhecem patógenos como bactérias, fungos e vírus. Como o processo inflamatório possui um importante papel em diversas doenças, os TLRs foram considerados potenciais alvos em estratégias terapêuticas, incluindo o tratamento de câncer. No entanto, o papel dos TLRs permanece ambíguo. Esse estudo teve como objetivos analisar os níveis de expressão dos TLRs presentes em membrana plasmática, TLRs (TLR1, TLR2, TLR4, TLR5, TLR6) em astrocitomas de diferentes graus de malignidade (grau II-IV), tumor mais prevalente do Sistema Nervoso Central (SNC). Nós demonstramos que a expressão dos TLRs foi mais alta em amostras de astrocitomas comparadas com tecido cerebral não-neoplásico, por qRT-PCR. A expressão gênica e proteica foi observada em células de linhagem de glioblastoma (GBM) U87MG e A172, mostrando sua presença em células tumorais. Foi observada expressão associada entre os heterodímeros TLR1- TLR2. Em GBMs, o subtipo mesenquimal mostrou maior nível de expressão dos TLRs comparados aos subtipos clássico e proneural. Com o objetivo de identificar o papel dos TLRs nas células tumorais, foi selecionado dentre os TLRs o que apresentou maior nível de expressão, o TLR4, e realizamos ensaios funcionais estimulando a U87MG com LPS, um agonista natural para TLR4. A taxa de proliferação da célula tratada com LPS foi similar a não tratada. No entanto, foi observado a ativação do NF-kB após 12hrs do estímulo com LPS. Quando a sinalização do receptor foi inibida por um composto químico (VGX-1027), o nível de proliferação da U87MG decaiu. Adicionalmente, análise in silico revelou uma forte associação dos TLRs hiperexpressos com aumento da expressão de genes relacionados à sinalização do ciclo celular, inflamassoma e ripoptossoma. O que sugere serem os TLRs alvos para complementação do tratamento do câncer
Toll-like receptors (TLRs) are the first to identify disturbances in the immune system, recognizing pathogens such as bacteria, fungi, and viruses. Since the inflammation process plays an important role in several diseases, TLRs have been considered potential therapeutic targets, including treatment for cancer. However, TLRs\' role in cancer remains ambiguous. This study aims to analyze the expression levels of plasmatic cell membrane TLRs (TLR1, TLR2, TLR4, TLR5, and TLR6) in different grades (II-IV) of human astrocytoma, the most prevalent tumor of CNS. We demonstrated that TLR expressions were higher in astrocytoma samples compared to non-neoplastic brain tissue, by qRT-PCR. The genes and proteins expressions were observed in U87MG and A172 GBM cell lines, proving their presence in the tumor cells. Associated expressions between the known heterodimers TLR1-TLR2 were found in diffusely infiltrative astrocytoma. In GBM, the mesenchymal subtype showed higher levels of TLR expressions in relation to classical and proneural subtypes. Aiming to indentify the role of TLRs in tumor cells, we chose the highest TLR expressed in GBM cells, the TLR4, and performed functional assays stimulating U87MG-GBM cell line with LPS, a natural agonist for TLR4. The proliferation rate was similar in treated and non-treated cell with LPS. However, NF-kB activation was detected after 12hrs of LPS stimulation. When TLR4 signaling pathway was inhibited by a chemical compound (VGX-1027) a decrease in the proliferation rate was observed. Additionally, in silico analysis revealed a strong association of TLRs upregulation with increased expression level of genes related to cell cycle, inflammasome and ripoptosome pathways, further highlighting TLRs as interesting targets for cancer complementary treatment

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Vicente-Suarez, Ildefonso. "Immunomodulatory role of flagellin in antigen-presenting cells". [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002201.

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Faria, Camila Cristina Quinello Gomes de. "Avaliação da resposta imune após estimulação de monócitos via Toll-Like Receptor 2 (TLR-2) em recém-nascidos a termo e pré-termo". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-04022014-105154/.

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O sistema imune neonatal tem sido considerado funcionalmente imaturo e recentes estudos sugerem que a suscetibilidade do neonato às infecções pode ser devido a alterações funcionais de células apresentadoras de antígenos que podem levar a deficiências secundárias nas respostas adaptativas. A ativação das células apresentadoras de antígenos é desencadeada pela estimulação de receptores, como os Toll-like Receptors (TLRs) e alterações na ativação desses receptores podem levar a uma subsequente redução da ativação de proteínas da via de sinalização intracelular e consequente alterações dos níveis das citocinas pró- e anti-inflamatórias, contribuindo assim, para uma resposta imune ineficiente do neonato. O Toll-like receptor 2 (TLR-2) é um receptor essencial para o reconhecimento seletivo de vários antígenos bacterianos e virais, em especial, o peptideoglicano, que compreende cerca de 50% da parede celular de bactérias Grampositivas, como os estafilococos, que são agentes infecciosos que prevalecem nas Unidades de Terapia Intensiva Neonatal. O objetivo deste estudo foi avaliar a ativação e resposta de monócitos de sangue do cordão umbilical de recém-nascidos pré-termo saudáveis < 34 semanas de gestação (Grupo 1), recém-nascidos pré-termo : 34 e < 37 semanas de gestação (Grupo 2) e recém-nascidos a termo (Grupo 3) e de adultos saudáveis, como controles, após a estimulação de TLR-2 ex-vivo com Pam3CSK4. Após a estimulação dos monócitos, foram determinados os níveis de expressão dos marcadores de ativação celular, os níveis das citocinas pró- e anti-inflamatórias e a expressão de moléculas envolvidas na sinalização intracelular. A caracterização das populações leucocitárias, bem como a capacidade fagocítica de Staphylococcus aureus e geração de burst oxidativo por monócitos e neutrófilos foram analisados por Citometria de Fluxo. Os resultados demonstraram que as células dendríticas e monócitos de neonatos expressam TLR-2 em níveis semelhantes aos de adultos. A expressão adequada de TLR-2 sugere um reconhecimento antigênico eficiente que é refletido em uma ativação apropriada das moléculas da cascata de sinalização e uma potente produção de citocinas pró-inflamatórias, apesar da reduzida produção de IL-10. Fagócitos neonatais apresentaram capacidade fagocítica de S. aureus reduzida em relação aos adultos e geração do burst oxidativo semelhante entre os grupos, no entanto neonatos prétermo apresentaram produção de peróxido de hidrogênio deficiente, o que poderia contribuir com uma reduzida morte intracelular deste microrganismo. Em conclusão, o recém-nascido não apresenta uma imaturidade funcional, mas sim, um desequilíbrio em sua resposta imune inata, com uma aparente menor produção de fatores antiinflamatórios, o que pode levar a predisposição à sepse
The neonatal immune system has been considered functionally immature and recent studies suggest that susceptibility of the neonate to infections may be due to functional alterations in antigen-presenting cells that can prompt to secondary deficiencies in adaptive responses. The activation of antigen-presenting cells is triggered by stimulation of receptors such as Toll-like receptors (TLRs) and changes in the activation of these receptors may lead to a subsequent reduction in the activation of intracellular signaling pathway proteins and consequent changes in pro- and anti-inflammatory cytokine levels, thus contributing to an inefficient immune response of the neonate. Toll-like Receptor 2 (TLR-2) is an essential receptor for the selective recognition of several bacterial and viral antigens, in particular, peptidoglycan, which comprises about 50% of the Gram-positive bacteria cell wall, such as staphylococci, which are infectious agents that prevail in Neonatal Intensive Care Units. The aim of this study was to evaluate the activation and response of monocytes derived from umbilical cord blood of healthy preterm newborns <34 weeks of gestation (Group 1), preterm newborns :34 and <37 weeks of gestation (Group 2) and term newborns (Group 3) and from healthy adults, as controls, after ex-vivo TLR-2 stimulation with Pam3CSK4. After monocyte stimulation, it was determined the expression levels of cellular activation markers, pro- and anti-inflammatory cytokine levels and the expression of molecules involved in downstream intracellular signaling. The characterization of leukocyte populations, as well as the phagocytic ability of Staphylococcus aureus and generation of oxidative burst by monocytes and neutrophils were analyzed by flow cytometry. The results demonstrated that neonatal dendritic cells and monocytes express TLR- 2 at similar levels to those of adults. The proper expression of TLR-2 suggests an efficient antigen recognition which is reflected in an appropriate activation of downstream signaling molecules and potent production of pro-inflammatory cytokines, in spite of the reduced production of IL-10. Neonatal phagocytes showed reduced phagocytic capacity of S. aureus compared to adults and similar generation of oxidative burst between groups, however preterm neonates showed deficient production of hydrogen peroxide, which could contribute to a reduced intracellular killing of this microorganism. In conclusion, the newborn does not present a functional immaturity, but an imbalance in its innate immune response, with an apparent lower production of antiinflammatory factors, which can lead to a predisposition to sepsis

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Lupica, Joseph A. "Inhibition of The NF-κB Signaling Pathway and Its Effects On Apoptosis and Cancer". Cleveland State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=csu1214235115.

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Bou, Karroum Nour. "Synthèse et développement de nouvelles molécules hétérocycliques tricycliques : étude de leurs propriétés immunomodulatrices". Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT014/document.

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Les récepteurs Toll-like 7 et 8 jouent un rôle important dans l’activation de la réponse immunitaire innée et adaptative. Leur stimulation conduit à la production des cytokines pro-inflammatoires et d’interférons de type I. L’imiquimod et son dérivé le résiquimod sont les premières molécules de faible poids moléculaire décrites comme agonistes du TLR7 et TLR8. Ces deux molécules ont montré des activités anticancéreuses et adjuvantes très importantes. Récemment, les TLR 7 et 8 ont fait l’objet de plusieurs publications visant à développer de nouveaux agonistes TLR7 et/ou TLR8 dans la perspective d’être utilisés comme adjuvants vaccinaux. Malgré les rôles essentiels de TLR7 et TLR8 dans la stimulation du système immunitaire, une activation immunitaire chronique peut être responsable de plusieurs maladies infectieuses et auto-immunes. D’où l’importance de développer également des antagonistes TLR7 et/ou TLR8.Ce travail de thèse est consacré à la synthèse et le développement de nouvelles molécules hétérocycliques, analogues de l’imiquimod et de résiquimod, dans le but d’identifier de nouveaux ligands TLR7 et/ou TLR8. Des voies de synthèse innovantes, permettant une modulation chimique importante grâce à des couplages croisés pallado-catalysés, ont été mises au point et ont permis d’obtenir une cinquantaine de molécules appartenant à trois séries chimiques différentes de type imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. De nombreux essais d’alkylation ont été tentés sur ces trois séries chimiques afin d’introduire une large variété de substituants sur le cycle à cinq sommets. L’application du couplage croisé de Sonogashira nous a permis d’établir une liaison C-C et introduire diverses chaines alkyles. Ces composés ont été testés pour leur activité agoniste et antagoniste TLR7 et 8. Aucun des composés cibles n'a présenté d’activité agoniste TLR7 et TLR8, dans l'intervalle des concentrations testées. Par contre, tous les composés ont montré une activité antagoniste sélective du TLR7. Les composés les plus actifs, 5.35a et 5.35b, membres de la série pyrazolo[1,5-a]quinoxaline ont montré des IC50 de l’ordre de 10 μM. Ces résultats prometteurs nous ont permis la découverte d’une activité antagoniste TLR7 importante pour la série pyrazolo[1,5-a]quinoxaline, une série très peu développée dans la littérature. La modulation chimique des molécules actives nous permet de donner naissance à de nouveaux leaders, qui peuvent jouer un rôle important dans la thérapie de plusieurs maladies infectieuses et auto-immunes
Toll-like receptors 7 and 8 play an important role in immune system activation. Their stimulation leads to the production of pro-inflammatory cytokines and type I interferons. Both receptors recognize viral ssRNA, as well as synthetic tricyclic imidazoquinoline derivatives such as imiquimod (TLR7 agonist) and resiquimod (TLR7/8 agonist). These two molecules showed significative anti-cancer and adjuvant activities. Many reports in the literature have been focused on the development of new TLR7/8 agonists belonging to different chemical series. These agonists strongly induce the production of T helper 1-polarizing cytokines and may therefore serve as promising candidate vaccine adjuvants. Despite the essential roles of TLR7 and TLR8 in the immune system stimulation, chronic immune activation may be responsible for several infectious and autoimmune diseases. Consequently, the development of TLR7 inhibitors may play an important role in the therapy of these diseases.In this study, we are interested in the synthesis and development of new heterocyclic molecules, analogs of imiquimod and resiquimod, in order to identify new TLR7 and/or TLR8 ligands. Different synthetic pathways have been developed, using cross coupling reactions, in order to obtain a wide variety of molecules belonging to three chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline et pyrazolo[1,5-a]quinoxaline. Various alkylation reactions were attempted on these three chemical series in order to introduce a wide variety of substituents on the five-membered ring. The application of Sonogashira's cross-coupling allowed us to establish a C-C bond and introduce various alkyl chains. All compounds have been tested for their TLR7/8 agonistic and antagonistic activity using HEK-Blue™-hTLR7/8 cells. The synthesized compounds are completely inactive as TLR7/8 agonists and are selective TLR7 antagonists. Two compounds of the pyrazolo[1,5-a]quinoxaline series, compound 5.35a and 5.35b, bearing butyl and isobutyl chain respectively, are potent and selective TLR7 antagonists with low micromolar IC50. Results allowed us to discover significative activity for the pyrazolo[1,5-a]quinoxaline series as selective TLR7 antagonists, which may therefore play an important role in the therapy of several infectious or autoimmune diseases

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Andersen-Nissen, Erica. "Toll-like receptor 5 recognition fo bacterial flagellin /". Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8341.

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Gibbard, R. J. "Understanding the initial activation of Toll-like receptor 5 and Toll-like receptor 8 by their ligands". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599370.

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The precise mechanism by which TLRs recognise their ligands and lead to downstream signalling is currently largely unclear. The major aim of this work was to begin to understand the nature of the interaction between human toll-like receptors and their ligands, using biochemical, structural, cell biological and fluorescence imaging techniques. This research aimed to elucidate the mechanism by which two TLRs recognise their ligands; TLR5 and its bacterial protein ligand flagellin and TLR8 and its viral ligand ssRNA and a synthetic ligand, resiquimod. Initial studies were to express and purify the extracellular domain of the receptors to generate purified protein to study the receptor/ligand interactions by biophysical and structural methods. Creating sufficiently pure protein in the baculovirus expression system was unachievable due to the fairly low levels of expression and the inability of insect cells to secrete the recombinant proteins. Alternative approaches to study the receptor/ligand interactions were pursued using cell based systems. This included the use of NF-κB reporter assays to study receptor activation in cells and fluorescent protein fusion receptors with confocal microscopy to determine the cellular localisation of the receptors in transiently transfected cells. Mutagenesis studies of TLR8 were also performed to determine residues that were critical for NF-κB activation and protein expression of these mutants was shown to be similar to wild-type receptors by microscopy. Förster resonance energy transfer (FRET) was performed to look at possible receptor/receptor interactions before and after stimulation with ligand in live cells. Fluorescent ligands were able to show the likely interaction site of receptor and ligand in transiently transfected cells. All together these techniques lead to insights as to how and where these two TLRs interact with their ligands and possible models for receptor/ligand interaction can now be proposed.

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Ferreira, Darkiane Fernandes. "Papel do receptor toll-like 4 no metabolismo lipídico hepático". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5167/tde-26112014-085554/.

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Estudos recentes têm demonstrado uma participação importante do receptor toll-like 4 (TLR4) na evolução de doenças envolvendo desordens metabólicas, como a doença do fígado gorduroso não-alcoólico (NAFLD). No entanto, as alterações do metabolismo lipídico que poderiam ser influenciadas pela ativação do TLR4 são desconhecidas. Neste estudo propomos caracterizar o papel do receptor TLR4 no metabolismo de lipídios no fígado de camundongos deficientes para o receptor de LDL, um modelo que desenvolve NAFLD quando submetido a uma dieta rica em gordura saturada e colesterol. Camundongos controle (C57 black6), deficientes para o receptor de LDL (LDLrKO), deficientes para o receptor TLR4 (TLR4KO) ou deficientes para ambos (duplo KO) receberam dieta controle ou hiperlipídica por quatro, oito ou doze semanas. Após o tratamento e sacrifício dos animais, avaliamos o perfil de lipídios plasmáticos, o conteúdo de lipídios do fígado e a expressão gênica de enzimas relacionadas à síntese e degradação de triglicerídeos (TG) e colesterol no fígado. O perfil inflamatório no fígado também foi avaliado. A dieta hiperlipídica induziu uma hipertrigliceridemia e hipercolesterolemia nos animais LDLr KO e duplo KO, sendo que o grupo duplo KO apresentou níveis séricos inferiores de triglicérides (TG) e ácidos graxos livres a partir de oito semanas de tratamento em comparação aos animais LDLrKO. A dieta hiperlipídica também induziu um aumento significativo no conteúdo de TG e de colesterol no fígado de todos os grupos. Na análise da expressão gênica não foram encontradas diferenças na expressão de proteínas relacionadas à síntese de triglicérides e colesterol (ApoB100, MTTP, GPAT1 e GPAT4) entre os grupos. Porém houve aumento significativo na expressão de proteínas relacionadas à oxidação de ácidos graxos (CPT1, MTP, ACOX, PBE, tiolase) e à síntese de ácidos biliares (CYP7a1) no grupo duplo KO em comparação ao grupo LDLr KO. No perfil inflamatório, a expressão de F4/80 demonstrou infiltração de macrófagos significativamente elevada no grupo LDLrKO tratado com a dieta hiperlipídica comparada a todos os outros grupos. No entanto, houve maior expressão de IL-6, IL-1beta e TNF-alfa no grupo duplo KO em comparação ao grupo LDLr KO. Nossos dados sugerem que a ativação do TLR4 no fígado de animais alimentados com uma dieta hiperlipídica pode contribuir para o acúmulo de lipídios e início da esteatose hepática. Estratégias para a inativação hepática do TLR4 podem diminuir a NAFLD não somente devido a diminuição da inflamação, mas por aumentar a oxidação de ácidos graxos no fígado
Recent studies have shown an important role of toll-like receptor 4 (TLR4) in the evolution of diseases involving metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD). However, changes in lipid metabolism regulated by TLR4 activation are still unknown. In this study, we characterized the role of TLR4 receptor in hepatic lipid metabolism of mice deficient for the LDL receptor, a model that develops NAFLD when exposed to a diet rich in saturated fat and cholesterol. We investigated the role of TLR4 activation in the pathogenesis of diet-induced NAFLD by crossing LDLr KO mice with the TLR4 knockout mice (double KO). Animals were fed for 4, 8 or 12 weeks with high-fat diet (HFD) containing 18% saturated fat and 1.25% cholesterol. We evaluated plasma lipid profile, hepatic lipid content and gene expression of enzymes related to the synthesis and degradation of triglycerides and cholesterol in the liver. Liver inflammatory status was also investigated. We observed that HFD induced hypertriglyceri-demia and hypercholesterolemia in LDLr KO and double KO mice, but double KO animals presented lower serum levels of triglycerides and free fatty acids after eight weeks of treatment. HFD also induced a significant increase in liver contents of triglycerides (TG) and of cholesterol in all groups. We did not find differences in the expression of proteins related to triglycerides and cholesterol synthesis (ApoB100, MTTP, GPAT1, GPAT4) between the groups. However, we observed a significant increase in the expression of proteins related to fatty acid oxidation (CPT1, MTP, ACOX, PBE, tiolase ) and bile acid synthesis (CYP7a1) in double KO group in comparison to LDLr KO. Regarding the inflammatory process, F4/80 expression was elevated in LDLr KO mice fed HFD when compared to all groups. On the other hand, IL-6, IL-1beta e TNF-alfa expression was induced by HFD only in double KO mice. Taken together, our results show that TLR4 activation in liver from mice fed on a high-fat diet may contribute to lipid accumulation and steatosis onset. Strategies regarding localized TLR4 inactivation may increase the oxidation of fatty acids and improve NAFLD not only due to decreased inflammation

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Atif, Shaikh M. "TLR5 (Toll-like Receptor 5)". En Encyclopedia of Signaling Molecules, 1–9. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4614-6438-9_639-1.

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Atif, Shaikh Muhammad. "TLR5 (Toll-Like Receptor 5)". En Encyclopedia of Signaling Molecules, 5484–92. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_639.

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Gonçalves, João, Helena Soares, Norman L. Eberhardt, Sarah C. R. Lummis, David R. Soto-Pantoja, David D. Roberts, Umadas Maitra et al. "Toll-like receptor 5". En Encyclopedia of Signaling Molecules, 1892. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_101388.

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Kandimalla, Ekambar R. y Sudhir Agrawal. "CHAPTER 5. Oligonucleotide-based Toll-like Receptor Antagonists and Therapeutic Applications". En Drug Discovery, 80–102. Cambridge: Royal Society of Chemistry, 2019. http://dx.doi.org/10.1039/9781788015714-00080.

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Smith, K. D. y A. Ozinsky. "Toll-Like Receptor-5 and the Innate Immune Response to Bacterial Flagellin". En Current Topics in Microbiology and Immunology, 93–108. Berlin, Heidelberg: Springer Berlin Heidelberg, 2002. http://dx.doi.org/10.1007/978-3-642-59430-4_6.

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Sharma, B. S., J. Mount y N. A. Karrow. "Functional Characterization of a Single Nucleotide Polymorphism in the 5’UTR Region of the Bovine Toll-like Receptor 4 Gene". En Animal Genomics for Animal Health, 331–36. Basel: KARGER, 2008. http://dx.doi.org/10.1159/000317179.

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Spyvee, Mark, Lynn D. Hawkins y Sally T. Ishizaka. "Modulators of Toll-Like Receptor (TLR) Signaling". En Annual Reports in Medicinal Chemistry, 191–207. Elsevier, 2010. http://dx.doi.org/10.1016/s0065-7743(10)45012-5.

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"Toll-Like Receptor 5". En Encyclopedia of Signaling Molecules, 5532. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_103907.

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Mandraju, R., T. D. Troutman y C. Pasare. "Toll-Like Receptor Function and Signaling". En Reference Module in Biomedical Sciences. Elsevier, 2014. http://dx.doi.org/10.1016/b978-0-12-801238-3.00104-5.

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Sifers, Travis M. y Venkatesh Sampath. "Monogenic Defects of Toll-Like Receptor Signaling and Primary Immunodeficiency". En Immunity and Inflammation in Health and Disease, 165–74. Elsevier, 2018. http://dx.doi.org/10.1016/b978-0-12-805417-8.00013-5.

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Actas de conferencias sobre el tema "Toll-like receptor 5 (TLR5)"

Wierzbicki, Andrzej J., Araba A. Adjei, Nuttapong Ngamphaiboon, Thanyanan Reungwetwattana, Andrei V. Gudkov y Alex A. Adjei. "Abstract 5492: Functional characterization of human toll-like receptor 5 (TLR5) genetic variants". En Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5492.

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Haughton, Nicola, Foster Emily, Christopher Womack, Simon Barry, Setsuko Yamamoto, Masashi Murata y Marie Cumberbatch. "Abstract 3670: Toll-like receptor (TLR) 7 expression in the human tumor microenvironment". En Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-3670.

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Paulus, Patrick, Anja Urbschat, Christin Reissig, Kai Zacharowski, Stefan Dröse, Bertram Scheller y Elisabeth Tybl. "Abstract 537: Toll-like receptor (TLR3) signaling in human hepatocellular carcinoma (HCC) depends on the tumor-associated long-noncoding RNA H19". En Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-537.

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Chinn, Jason, Crystal Cummings, Felecia Wagener, Shaarwari Sridhar, Kien Khuu-Duong, Xinhui Ge, Karen Yoshino et al. "Abstract B18: Combining selective toll-like receptor 9 (TLR9) agonists and GM-CSF activity for potentiating cellular activation in active cell immunotherapy (ACI)." En Abstracts: AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; December 2-5, 2012; Miami, FL. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.tumimm2012-b18.

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Muccioli, Maria, Michelle Pate y Fabian Benencia. "Abstract A65: Toll-like receptor 3 signaling in ovarian cancer." En Abstracts: AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; December 2-5, 2012; Miami, FL. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.tumimm2012-a65.

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Muramatsu, Soshi, Tsutomu Tamada, Masayuki Nara, Koji Murakami, Shigeki Chiba, Toshiaki Kikuchi, Masahito Ebina y Toshihiro Nukiwa. "Toll-Like Receptor 5 Potentiates Ca2+-Dependent Electrolytes Secretion From Airway Submucosal Gland". En American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4275.

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Kohtz, Patrick. "Abstract 4637: Activation of toll-like receptor-2 promotes proliferation in human lung adenocarcinoma cells". En Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4637.

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Li, Peng, Xin Du, Yun Xin, Jianyu Weng y Peilong Lai. "Abstract 618: Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells". En Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-618.

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Brackett, Craig, Bojidar Kojouharov, Sandra Gollnick, Andrei Gudkov y Lyudmila Burdelya. "Abstract B090: A Toll-like receptor 5 agonist entolimod as a potential anticancer immunotherapeutic agent". En Abstracts: CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr15-b090.

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Xu, Wenwen, Ying Yuan, Na Li, Yongwei Zheng, Kamal Rajasekaran, Halli Miller, Michael Olson, Demin Wang, Subramaniam Malarkannan y Li Wang. "Abstract 2996: Immune checkpoint protein VISTA suppresses Toll-like receptor signaling and the production of inflammatory cytokines". En Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2996.

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