Journal articles: 'TLR signaling'

1

Kawai, Taro, and Shizuo Akira. "TLR signaling." Seminars in Immunology 19, no. 1 (February 2007): 24–32. http://dx.doi.org/10.1016/j.smim.2006.12.004.

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Kawai, T., and S. Akira. "TLR signaling." Cell Death & Differentiation 13, no. 5 (January 20, 2006): 816–25. http://dx.doi.org/10.1038/sj.cdd.4401850.

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Takeda, Kiyoshi, and Shizuo Akira. "TLR signaling pathways." Seminars in Immunology 16, no. 1 (February 2004): 3–9. http://dx.doi.org/10.1016/j.smim.2003.10.003.

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Brown, J., H. Wang, G. N. Hajishengallis, and M. Martin. "TLR-signaling Networks." Journal of Dental Research 90, no. 4 (October 12, 2010): 417–27. http://dx.doi.org/10.1177/0022034510381264.

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O'Neill, Luke A. J. "'Fine tuning' TLR signaling." Nature Immunology 9, no. 5 (May 2008): 459–61. http://dx.doi.org/10.1038/ni0508-459.

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Gough, N. R. "Stages of TLR Signaling." Science Signaling 1, no. 21 (May 27, 2008): ec195-ec195. http://dx.doi.org/10.1126/stke.121ec195.

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TAMAKI, YASUNOBU, YUYA TAKAKUBO, TOMOYUKI HIRAYAMA, YRJÖ T. KONTTINEN, STUART B. GOODMAN, MITSUNORI YAMAKAWA, and MICHIAKI TAKAGI. "Expression of Toll-like Receptors and Their Signaling Pathways in Rheumatoid Synovitis." Journal of Rheumatology 38, no. 5 (February 15, 2011): 810–20. http://dx.doi.org/10.3899/jrheum.100732.

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Objective.Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters.Methods.TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining.Results.In RA, ß-actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells.Conclusion.RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.

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Jeyaseelan, Samithamby. "How TLR signaling is regulated." Trends in Microbiology 10, no. 10 (October 2002): 448. http://dx.doi.org/10.1016/s0966-842x(02)02448-4.

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VanHook, Annalisa M. "TLR signaling mediates pathogen avoidance." Science Signaling 8, no. 393 (September 8, 2015): ec254-ec254. http://dx.doi.org/10.1126/scisignal.aad3632.

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van Duin, David, Ruslan Medzhitov, and Albert C. Shaw. "Triggering TLR signaling in vaccination." Trends in Immunology 27, no. 1 (January 2006): 49–55. http://dx.doi.org/10.1016/j.it.2005.11.005.

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Mistry, Pragnesh, Michelle H. W. Laird, Ryan S. Schwarz, Shannon Greene, Tristan Dyson, Greg A. Snyder, Tsan Sam Xiao, et al. "Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain." Proceedings of the National Academy of Sciences 112, no. 17 (April 13, 2015): 5455–60. http://dx.doi.org/10.1073/pnas.1422576112.

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Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein–protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4(C29) was identified as a potential TLR2 inhibitor. C29, and its derivative,ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated witho-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors.

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Tolba, Khaled A., William Bowers, Yaohong Tan, Sandrine Daubeuf, Howard J. Federoff, and Joseph D. Rosenblatt. "HSV ICP0 Inhibits TLR-Mediated NF-κB Response to TLR Signaling." Blood 108, no. 11 (November 16, 2006): 5487. http://dx.doi.org/10.1182/blood.v108.11.5487.5487.

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Abstract HSV infection activates a robust innate response through engagement of multiple pattern recognition receptors (PRR) including both TLR (TLR2 and TLR9) as well as non-TLR. Signaling events downstream of these receptors activate NF-κB and IRF3 responsive genes and initiate an innate inflammatory response aimed at controlling viral replication and spread. In this work, we studied immune suppressive activity of a replication-defective HSV virus and identified the immediate early protein ICP0 as a negative regulator of both NF-κB and IRF3 signaling. ICP0 possesses an ubiquitin E3 ligase function through its NH2 RING domain, as well as de-ubiquitinating activity through its association with the cellular de-ubiquitinating enzyme USP7 (HAUSP). We show that these two domains of ICP0 function independently to suppress IRF3 and NF-κB signaling, respectively and, in the process, effectively shut down host innate immunity to HSV infection. Although ICP0 inhibition of IRF3 has been reported, inhibition of TLR-mediated NF-κB response has not been previously described. We show that ICP0 globally inhibits NF-κB response to all TLR receptors as well as IL-1R. ICP0 exerts this activity by associating with USP7 and altering its cellular localization from a nuclear to cytoplasmic protein. In the cytosol, USP7 associates with and de-ubiquitinates TRAF6 and IKK-γ (NEMO), two signaling components of the TLR-mediated NF-κB pathway that are poly-ubiquitinated upon TLR activation. ICP-0 expression vectors harboring point mutations/deletions that target the RING domain E3 ligase function or compromise ICP-0 ability to bind USP7 would selectively inhibit its ability to interfere with either IRF3 or NF-kB signaling, respectively. In support of this, knockdown of endogenous USP7 by RNAi severely impaired ICP0-mediated inhibition of NF-κB response while leaving its capacity to inhibit IRF3 intact. In contrast, over-expression of USP-7 was sufficient to inhibit TLR-mediated NF-κB response. Ability of ICP-0 to inhibit both IRF3 and NF-κB signaling pathways, the former through its E3 ligase function and the latter through its association with USP-7, affords HSV comprehensive protection from host immunity during repeated cycles of lytic infection and reactivation from latency. The work also identifies a rare example of how two seemingly contradictory biologic functions resident within ICP0, namely ubiquitin E3 ligase activity at the NH2 terminus RING domain and de-ubiquitinating activity through association with USP-7, could cooperate to inhibit multiple signaling pathways necessary for efficient silencing of innate immunity. Finally, the work also identifies a previously unknown function for USP7 in regulating innate signaling beyond its known function as a regulator of p53.

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Fekonja, Ota, Monika Avbelj, and Roman Jerala. "Suppression of TLR Signaling by Targeting TIR domain-Containing Proteins." Current Protein and Peptide Science 13, no. 8 (December 1, 2012): 776–88. http://dx.doi.org/10.2174/138920312804871148.

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14

Yamamoto, M. "TIR domain-containing adaptors define the specificity of TLR signaling." Molecular Immunology 40, no. 12 (February 2004): 861–68. http://dx.doi.org/10.1016/j.molimm.2003.10.006.

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Tan, Yaohong, Joseph D. Rosenblatt, Howard J. Federoff, William J. Bowers, and Khaled A. Tolba. "Regulation of TLR Signaling by USP7." Blood 110, no. 11 (November 16, 2007): 2300. http://dx.doi.org/10.1182/blood.v110.11.2300.2300.

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Abstract USP7 is a 1102 animo acid de-ubiquitinating enzyme (DUB) that belongs to the ubiquitin-specific protease (USP) family. By virtue of its interaction with the tumor suppressor p53 and its negative regulator MDM2, USP7 plays a key role in regulation of cell survival and stress response. USP7 also interacts with two viral proteins, namely HSV-1 ICP0 and EBV EBNA-1, however the precise significance of this has not been fully understood. We have previously shown that HSV-1 ICP0 specifically inhibits TLR-mediated innate response to viral infection. In this work, we further investigated this observation, showing that ICP0 recruits USP7, a nuclear protein to the peri-nuclear zone where the latter interacts with TRAF6 and IKKγ. USP7 interaction with TRAF6 and IKKγ were mediated by its amino terminal TRAF domain and resulted in de-ubiquitination of both TRAF6 and IKKγ. Over-expression of USP7 but not the catalytically-inactive mutant C223S (where the active site cysteine was mutated to serine) inhibited TLR response by de-ubiquitinating both TRAF6 and IKKγ, and this effect was augmented by co-expression of ICP0. On the other hand, RNAi-mediated knock-down of endogenous USP7 augmented TLR response, comparable to that seen with A20 and Cyld knockdown and suggesting a significant degree of redundancy at the level of DUB-mediated regulation of TLR signaling. Confocal microscopy showed that association between ICP0 and USP7 alters the sub-cellular localization of USP7 from nuclear to cytoplasmic where it predominantly accumulates in the peri-nuclear region. We hypothesized that translocation of USP7 from nuclear to cytosolic would bring it into close proximity of its two substrates, TRAF6 and IKKγ. In support of this, over-expression of a modified USP7 encoding a nuclear-export signal (NES) and thus expressed in both cytosol and nucleus was associated with enhanced ability to suppress TLR response and de-ubiquitinate IKKγ. In summary, our results identify a novel function for the de-ubiquitinating enzyme USP7 as well as reveal an additional mechanism by which HSV evades host innate immunity.

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Heeg, Klaus. "SOCS-MEDIATED REGULATION OF TLR-SIGNALING." Shock 21, Supplement (March 2004): 11. http://dx.doi.org/10.1097/00024382-200403001-00041.

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Ippagunta, Sirish K., Julie A. Pollock, Naina Sharma, Wenwei Lin, Taosheng Chen, Kazuki Tawaratsumida, Anthony A. High, et al. "Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins." Science Signaling 11, no. 543 (August 14, 2018): eaaq1077. http://dx.doi.org/10.1126/scisignal.aaq1077.

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Toll-like receptors (TLRs) recognize various pathogen- and host tissue–derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs and the cytoplasmic adaptor proteins TIRAP and MyD88. Oligomerization of TLRs with MyD88 or TIRAP leads to the recruitment of members of the IRAK family of kinases and the E3 ubiquitin ligase TRAF6. We developed a phenotypic drug screening system based on the inducible homodimerization of either TIRAP, MyD88, or TRAF6, that ranked hits according to their hierarchy of action. From a bioactive compound library, we identified methyl-piperidino-pyrazole (MPP) as a TLR-specific inhibitor. Structure-activity relationship analysis, quantitative proteomics, protein-protein interaction assays, and cellular thermal shift assays suggested that MPP targets the TIR domain of MyD88. Chemical evolution of the original MPP scaffold generated compounds with selectivity for distinct TLRs that interfered with specific TIR interactions. Administration of an MPP analog to mice protected them from TLR4-dependent inflammation. These results validate this phenotypic screening approach and suggest that the MPP scaffold could serve as a starting point for the development of anti-inflammatory drugs.

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Gruber, Erika J., and Cynthia A. Leifer. "Molecular regulation of TLR signaling in health and disease: mechano-regulation of macrophages and TLR signaling." Innate Immunity 26, no. 1 (January 2020): 15–25. http://dx.doi.org/10.1177/1753425919838322.

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Immune cells encounter tissues with vastly different biochemical and physical characteristics. Much of the research emphasis has focused on the role of cytokines and chemokines in regulating immune cell function, but the role of the physical microenvironment has received considerably less attention. The tissue mechanics, or stiffness, of healthy tissues varies dramatically from soft adipose tissue and brain to stiff cartilage and bone. Tissue mechanics also change due to fibrosis and with diseases such as atherosclerosis or cancer. The process by which cells sense and respond to their physical microenvironment is called mechanotransduction. Here we review mechanotransduction in immunologically important diseases and how physical characteristics of tissues regulate immune cell function, with a specific emphasis on mechanoregulation of macrophages and TLR signaling.

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Brennan, Joseph J., Jonathan L. Messerschmidt, Leah M. Williams, Bryan J. Matthews, Marinaliz Reynoso, and Thomas D. Gilmore. "Sea anemone model has a single Toll-like receptor that can function in pathogen detection, NF-κB signal transduction, and development." Proceedings of the National Academy of Sciences 114, no. 47 (November 6, 2017): E10122—E10131. http://dx.doi.org/10.1073/pnas.1711530114.

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In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone Nematostella vectensis is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-κB pathway. We have characterized the single N. vectensis TLR (Nv-TLR) and demonstrated that it can activate canonical NF-κB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv-TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen Vibrio coralliilyticus causes a rapidly lethal disease in N. vectensis and that heat-inactivated V. coralliilyticus and bacterial flagellin can activate a reconstituted Nv-TLR–to–NF-κB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR–expressing cells also express Nv-NF-κB. Additionally, the nematosome, which is a Nematostella-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf V. coralliilyticus. Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for N. vectensis reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity.

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Litak, Jakub, Cezary Grochowski, Joanna Litak, Ida Osuchowska, Krzysztof Gosik, Elżbieta Radzikowska, Piotr Kamieniak, and Jacek Rolinski. "TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives." International Journal of Molecular Sciences 21, no. 9 (April 28, 2020): 3114. http://dx.doi.org/10.3390/ijms21093114.

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Toll-like-receptor (TLR) family members were detected in the central nervous system (CNS). TLR occurrence was noticed and widely described in glioblastomamultiforme (GBM) cells. After ligand attachment, TLR-4 reorients domains and dimerizes, activates an intracellular cascade, and promotes further cytoplasmatic signaling. There is evidence pointing at a strong relation between TLR-4 signaling and micro ribonucleic acid (miRNA) expression. The TLR-4/miRNA interplay changes typical signaling and encourages them to be a target for modern immunotherapy. TLR-4 agonists initiate signaling and promote programmed death ligand-1 (PD-1L) expression. Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression. Another potential target for immunotreatment is connected with limited TLR-4 signaling that promotes Wnt/DKK-3/claudine-5 signaling, resulting in a limitation of GBM invasiveness. Interestingly, TLR-4 expression results in bordering proliferative trends in cancer stem cells (CSC) and GBM. All of these potential targets could bring new hope for patients suffering from this incurable disease. Clinical trials concerning TLR-4 signaling inhibition/promotion in many cancers are recruiting patients. There is still a lot to do in the field of GBM immunotherapy.

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Kawagoe, Tatsukata, Shintaro Sato, Andreas Jung, Masahiro Yamamoto, Kosuke Matsui, Hiroki Kato, Satoshi Uematsu, Osamu Takeuchi, and Shizuo Akira. "Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling." Journal of Experimental Medicine 204, no. 5 (May 7, 2007): 1013–24. http://dx.doi.org/10.1084/jem.20061523.

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Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

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Burns, Kimberly, Sophie Janssens, Brian Brissoni, Natalia Olivos, Rudi Beyaert, and Jürg Tschopp. "Inhibition of Interleukin 1 Receptor/Toll-like Receptor Signaling through the Alternatively Spliced, Short Form of MyD88 Is Due to Its Failure to Recruit IRAK-4." Journal of Experimental Medicine 197, no. 2 (January 13, 2003): 263–68. http://dx.doi.org/10.1084/jem.20021790.

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Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-κB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-κB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-κB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.

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Yin, Shasha, and Wangsen Cao. "Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation." Molecular and Cellular Biology 35, no. 15 (May 26, 2015): 2673–83. http://dx.doi.org/10.1128/mcb.00105-15.

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Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.

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Aluri, Jahnavi, Megan A. Cooper, and Laura G. Schuettpelz. "Toll-Like Receptor Signaling in the Establishment and Function of the Immune System." Cells 10, no. 6 (June 2, 2021): 1374. http://dx.doi.org/10.3390/cells10061374.

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Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.

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Fukao, Taro, and Shigeo Koyasu. "PI3K and negative regulation of TLR signaling." Trends in Immunology 24, no. 7 (July 2003): 358–63. http://dx.doi.org/10.1016/s1471-4906(03)00139-x.

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Abreu, Maria T., Lisa S. Thomas, Elizabeth T. Arnold, Katie Lukasek, Kathrin S. Michelsen, and Moshe Arditi. "TLR signaling at the intestinal epithelial interface." Journal of Endotoxin Research 9, no. 5 (October 1, 2003): 322–30. http://dx.doi.org/10.1179/096805103225002593.

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Salomão, Reinaldo, Paulo Sérgio Martins, Milena Karina Colo Brunialti, Maria da Luz Fernandes, Leandro S. W. Martos, Marialice Erdelyi Mendes, Natália E. Gomes, and Otelo Rigato. "TLR SIGNALING PATHWAY IN PATIENTS WITH SEPSIS." Shock 30, Suppl 1 (October 2008): 73–77. http://dx.doi.org/10.1097/shk.0b013e318181af2a.

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Gowda, D. Channe. "TLR-mediated cell signaling by malaria GPIs." Trends in Parasitology 23, no. 12 (December 2007): 596–604. http://dx.doi.org/10.1016/j.pt.2007.09.003.

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Meylan, Etienne, and Jürg Tschopp. "IRAK2 takes its place in TLR signaling." Nature Immunology 9, no. 6 (June 2008): 581–82. http://dx.doi.org/10.1038/ni0608-581.

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Nahid, Md A., Minoru Satoh, and Edward KL Chan. "MicroRNA in TLR signaling and endotoxin tolerance." Cellular & Molecular Immunology 8, no. 5 (August 8, 2011): 388–403. http://dx.doi.org/10.1038/cmi.2011.26.

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Balka, Katherine R., and Dominic Nardo. "Understanding early TLR signaling through the Myddosome." Journal of Leukocyte Biology 105, no. 2 (September 26, 2018): 339–51. http://dx.doi.org/10.1002/jlb.mr0318-096r.

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Abreu, Maria T., Lisa S. Thomas, Elizabeth T. Arnold, Katie Lukasek, Kathrin S. Michelsen, and Moshe Arditi. "TLR signaling at the intestinal epithelial interface." Journal of Endotoxin Research 9, no. 5 (October 2003): 322–30. http://dx.doi.org/10.1177/09680519030090050901.

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Marron, T. U. "The Role of BTK in TLR Signaling." Journal of Allergy and Clinical Immunology 123, no. 2 (February 2009): S92. http://dx.doi.org/10.1016/j.jaci.2008.12.329.

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Meyer-Bahlburg, Almut, and David J. Rawlings. "B cell autonomous TLR signaling and autoimmunity." Autoimmunity Reviews 7, no. 4 (February 2008): 313–16. http://dx.doi.org/10.1016/j.autrev.2007.11.027.

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Oosenbrug, Timo, Michel J. van de Graaff, Maaike E. Ressing, and Sander I. van Kasteren. "Chemical Tools for Studying TLR Signaling Dynamics." Cell Chemical Biology 24, no. 7 (July 2017): 801–12. http://dx.doi.org/10.1016/j.chembiol.2017.05.022.

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López-Haber, Cynthia, Roni Levin-Konigsberg, Yueyao Zhu, Jing Bi-Karchin, Tamas Balla, Sergio Grinstein, Michael S. Marks, and Adriana R. Mantegazza. "Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells." Proceedings of the National Academy of Sciences 117, no. 45 (October 27, 2020): 28251–62. http://dx.doi.org/10.1073/pnas.2001948117.

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Toll-like receptor (TLR) recruitment to phagosomes in dendritic cells (DCs) and downstream TLR signaling are essential to initiate antimicrobial immune responses. However, the mechanisms underlying TLR localization to phagosomes are poorly characterized. We show herein that phosphatidylinositol-4-kinase IIα (PI4KIIα) plays a key role in initiating phagosomal TLR4 responses in murine DCs by generating a phosphatidylinositol-4-phosphate (PtdIns4P) platform conducive to the binding of the TLR sorting adaptor Toll-IL1 receptor (TIR) domain-containing adaptor protein (TIRAP). PI4KIIα is recruited to maturing lipopolysaccharide (LPS)-containing phagosomes in an adaptor protein-3 (AP-3)-dependent manner, and both PI4KIIα and PtdIns4P are detected on phagosomal membrane tubules. Knockdown of PI4KIIα—but not the related PI4KIIβ—impairs TIRAP and TLR4 localization to phagosomes, reduces proinflammatory cytokine secretion, abolishes phagosomal tubule formation, and impairs major histocompatibility complex II (MHC-II) presentation. Phagosomal TLR responses in PI4KIIα-deficient DCs are restored by reexpression of wild-type PI4KIIα, but not of variants lacking kinase activity or AP-3 binding. Our data indicate that PI4KIIα is an essential regulator of phagosomal TLR signaling in DCs by ensuring optimal TIRAP recruitment to phagosomes.

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Marcondes, Maria Cecilia Garibaldi, Celsa Spina, Eduardo Bustamante, and Howard Fox. "Increased Toll-Like Receptor Signaling Pathways Characterize CD8+ Cells in Rapidly Progressive SIV Infection." BioMed Research International 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/796014.

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Similar to HIV infection in humans, SIV infection in macaques induces progressive loss of immune cell components and function, resulting in immune deficiency in nearly all untreated infected subjects. In SIV-infected macaques, 25% of animals develop terminal AIDS within 6 months of infection. The factors responsible for the development of such rapid progression are unknown. We have previously found that defects in CD8+ T cells detectable from early infection correlate to rapid progression to simian AIDS. The transcriptional screening of molecular fingerprints on different steps along the activation/effector process of splenic CD8+ cells at termination revealed a distinction in rapid compared to regular progressors, which was characterized by a decrease in classic T cell receptor (TCR) components, and an increase in Toll-like receptor (TLR) and apoptotic pathways. A TLR pathway screening in lymphoid and myeloid cells from both the spleen and from the central nervous system of infected macaques revealed that the upregulation of TLR is not in the innate immune compartment, but rather in lymphoid cells that contain adaptive immune cells. Our findings suggest that opposing effects of TCR specific signaling and TLR engagement may drive the CD8 phenotypic failure that determines a rapid disease course in HIV infection.

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Herman, Sarah E. M., Erin M. McAuley, Deanna H. Wong, Clare Sun, Delong Liu, and Adrian Wiestner. "Ibrutinib Inhibits Both B-Cell Receptor and Toll-like Receptor Signaling in Chronic Lymphocytic Leukemia." Blood 126, no. 23 (December 3, 2015): 313. http://dx.doi.org/10.1182/blood.v126.23.313.313.

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Abstract Chronic lymphocytic leukemia (CLL) cells rely on signals from the microenvironment to for cell activation, proliferation and survival. Microarray analysis of CLL cells harvested from patient-matched lymph node and peripheral blood demonstrated an up-regulation of B-cell receptor (BCR) signaling in the tissue microenvironment (Herishanu, Blood 2011). Concurrent with increased BCR signaling a dynamic increase in NF-κB signaling was also noted in the activated CLL cells in the tissue microenvironment (Herishanu, Blood 2011). As NF-κB can be activated downstream of multiple signaling pathways, in addition to the BCR, we sought to determine the role of alternative pathways on NF-κB activation. In gene expression analysis of CD19+ selected CLL cells, we found that in addition to an increase in BCR signaling the Toll-like receptor (TLR) signaling pathway was also significantly up-regulated in CLL cells in the lymph node microenvironment compared to circulating CLL cells. Activation of TLR signaling can cooperate with BCR signaling to overcome anergy and promote the expansion of auto-reactive B-cells (Leadbetter, Nature 2002). In addition, TLR signaling can induce proliferation of CLL cells and upregulates co-stimulatory molecules that may make CLL cells more effective antigen presenting cells. The latter effect has been explored as a therapeutic strategy to enhance the efficacy of immunotherapy of CLL by rendering CLL cells more susceptible to attack by cytotoxic T-cells (Spaner and Masellis, Leukemia 2007). We hypothesize that inhibition of TLR signaling could contribute directly to anti-leukemic effects by inhibiting survival and proliferation pathways. To test the effect of TLR signaling in CLL, CLL PBMCs were stimulated in vitro with a CpG oligonucleotide, which activates TLR9, for 6 hours. Increased pIκBα expression along with significant increases in pSTAT3 (P=0.001), IL-10 production (P=0.008) and up-regulation of the cell surface activation markers CD54, CD69 and CD86 (P<0.001) were observed, consistent with activation of TLR signaling. In order to evaluate the effect of inhibiting TLR signaling on CLL cells, we utilized an inhibitor of IRAK1/4 (EMD Chemicals), which acts directly downstream of MyD88. As expected, inhibition of IRAK1/4 significantly reduced TLR signaling in CpG stimulated CLL cells, resulting in decreased NF-κB signaling, IL-10 secretion (P=0.03) and phosphorylation of STAT3 (P<0.001) in drug treated compared to vehicle treated cells. Concurrently, inhibition of proliferation (as measured by Ki67) and tumor cell activation (CD69 and CD86 expression) was observed (P <0.05), demonstrating a direct anti-leukemic effect. Recently, the BTK inhibitor ibrutinib was shown to be clinically active in Waldenstrom's macrogloublinemia (WM), a chronic B-cell malignancy not dissimilar to CLL that is characterized by mutations in the TLR adaptor MyD88 (Treon, NEJM 2012; Treon, NEJM 2015). We therefore investigated whether ibrutinib could inhibit TLR signaling in CLL cells. Indeed, even at doses as low as 100nM, ibrutinib significantly inhibited CpG dependent activation of NF-κB signaling (P<0.05), downstream secretion of IL-10 (P<0.05) and phosphorylation of STAT3 (P<0.01). Additionally, proliferation (Ki67) and cellular activation induced by CpG were inhibited by ibrutinib treatment (P<0.05). Notably, both the inhibition of TLR signaling and the anti-tumor effect of ibrutinib at 100nM was comparable to inhibition achieved with 10µM of the IRAK1/4 inhibitor. In summary, TLR signaling is engaged in CLL cells in the lymph node microenvironment and upregulates proliferation and survival pathways. Ibrutinib appears to be as effective as a direct IRAK inhibitor in blocking TLR signaling in CLL cells, suggesting that treatment with ibrutinib is sufficient to inhibit both BCR and TLR signaling. This work was supported by the Intramural Research Program of National Heart Lung and Blood Institute of the National Institutes of Health. Disclosures Wiestner: Pharmacyclics: Research Funding.

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Yamamoto, Masahiro, and Kiyoshi Takeda. "Current Views of Toll-Like Receptor Signaling Pathways." Gastroenterology Research and Practice 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/240365.

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On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs) play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR) domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.

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West, Michele A., Alan R. Prescott, Kui Ming Chan, Zhongjun Zhou, Stefan Rose-John, Jürgen Scheller, and Colin Watts. "TLR ligand–induced podosome disassembly in dendritic cells is ADAM17 dependent." Journal of Cell Biology 182, no. 5 (September 1, 2008): 993–1005. http://dx.doi.org/10.1083/jcb.200801022.

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Toll-like receptor (TLR) signaling induces a rapid reorganization of the actin cytoskeleton in cultured mouse dendritic cells (DC), leading to enhanced antigen endocytosis and a concomitant loss of filamentous actin–rich podosomes. We show that as podosomes are lost, TLR signaling induces prominent focal contacts and a transient reduction in DC migratory capacity in vitro. We further show that podosomes in mouse DC are foci of pronounced gelatinase activity, dependent on the enzyme membrane type I matrix metalloprotease (MT1-MMP), and that DC transiently lose the ability to degrade the extracellular matrix after TLR signaling. Surprisingly, MMP inhibitors block TLR signaling–induced podosome disassembly, although stimulated endocytosis is unaffected, which demonstrates that the two phenomena are not obligatorily coupled. Podosome disassembly caused by TLR signaling occurs normally in DC lacking MT1-MMP, and instead requires the tumor necrosis factor α–converting enzyme ADAM17 (a disintegrin and metalloprotease 17), which demonstrates a novel role for this “sheddase” in regulating an actin-based structure.

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Wang, Jin, Anatoly V. Grishin, and Henri R. Ford. "Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96." Journal of Immunology 196, no. 12 (May 18, 2016): 5130–37. http://dx.doi.org/10.4049/jimmunol.1502135.

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van Tongeren, Joost, Korneliusz Golebski, Danielle Van Egmond, Esther J. de Groot, Wytske J. Fokkens, and Cornelis M. van Drunen. "Synergy between TLR-2 and TLR-3 signaling in primary human nasal epithelial cells." Immunobiology 220, no. 4 (April 2015): 445–51. http://dx.doi.org/10.1016/j.imbio.2014.11.004.

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Pahlavanneshan, Saghar, Ali Sayadmanesh, Hamidreza Ebrahimiyan, and Mohsen Basiri. "Toll-Like Receptor-Based Strategies for Cancer Immunotherapy." Journal of Immunology Research 2021 (May 22, 2021): 1–14. http://dx.doi.org/10.1155/2021/9912188.

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Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

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Loegering, Daniel J., and Michelle R. Lennartz. "Protein Kinase C and Toll-Like Receptor Signaling." Enzyme Research 2011 (August 23, 2011): 1–7. http://dx.doi.org/10.4061/2011/537821.

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Protein kinase C (PKC) is a family of kinases that are implicated in a plethora of diseases, including cancer and cardiovascular disease. PKC isoforms can have different, and sometimes opposing, effects in these disease states. Toll-like receptors (TLRs) are a family of pattern recognition receptors that bind pathogens and stimulate the secretion of cytokines. It has long been known that PKC inhibitors reduce LPS-stimulated cytokine secretion by macrophages, linking PKC activation to TLR signaling. Recent studies have shown that PKC-α, -δ, -ε, and -ζ are directly involved in multiple steps in TLR pathways. They associate with the TLR or proximal components of the receptor complex. These isoforms are also involved in the downstream activation of MAPK, RhoA, TAK1, and NF-κB. Thus, PKC activation is intimately involved in TLR signaling and the innate immune response.

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Singh, Joy Carmelina Indira, Sheena Margaret Cruickshank, Darren James Newton, Louise Wakenshaw, Anne Graham, Jinggang Lan, Jeremy Peter Alan Lodge, Peter John Felsburg, and Simon Richard Carding. "Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 3 (March 2005): G514—G524. http://dx.doi.org/10.1152/ajpgi.00377.2004.

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The interleukin-2-deficient (IL-2−/−) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2−/−mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2−/−mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-κB (p65) activation with the inhibitory p50 form of NF-κB predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.

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Yang, Mingjin, Chen Wang, Xuhui Zhu, Songqing Tang, Liyun Shi, Xuetao Cao, and Taoyong Chen. "E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKCζ." Journal of Experimental Medicine 208, no. 10 (September 12, 2011): 2099–112. http://dx.doi.org/10.1084/jem.20102667.

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The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)–interacting protein (CHIP, also known as Stub1) is a U box–containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4– and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C ζ (PKCζ) to the TLR complex, thereby leading to activation of IL-1 receptor–associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 and 7. CHIP acts as an E3 ligase for Src and PKCζ during TLR signaling. CHIP-mediated enhancement of TLR signaling is inhibited by IFNAR deficiency or expression of ubiquitination resistant mutant forms of Src or PKCζ. These findings suggest that CHIP facilitates the formation of a TLR signaling complex by recruiting, ubiquitinating, and activating Src and PKCζ.

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Zhu, Jiankun, and Chandra Mohan. "Toll-Like Receptor Signaling Pathways—Therapeutic Opportunities." Mediators of Inflammation 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/781235.

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Toll-like receptors (TLRs) are transmembrane proteins acting mainly as sensors of microbial components. Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection. However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity. Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways. This article reviews the role of these molecules in TLR signaling, and discusses the impact of this pathway on various disease scenarios. Given their important role in infectious and non-infectious disease settings, TLRs and their signaling pathways emerge as attractive targets for therapeutics.

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Buchta, Claire M., and Gail A. Bishop. "TRAF5 Negatively Regulates TLR Signaling in B Lymphocytes." Journal of Immunology 192, no. 1 (November 20, 2013): 145–50. http://dx.doi.org/10.4049/jimmunol.1301901.

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Zhang, Jiyan, and Beifen Shen. "SHP limits TLR signaling, an inducible transcriptional corepressor." Cellular & Molecular Immunology 8, no. 6 (August 22, 2011): 445–46. http://dx.doi.org/10.1038/cmi.2011.31.

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Hua, Zhaolin, and Baidong Hou. "TLR signaling in B-cell development and activation." Cellular & Molecular Immunology 10, no. 2 (December 17, 2012): 103–6. http://dx.doi.org/10.1038/cmi.2012.61.

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Journal articles on the topic 'TLR signaling'

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