Academic literature on the topic 'Endosomal TLRs'
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Journal articles on the topic "Endosomal TLRs"
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Sato, Ryota, Tatjana Reuter, Ryosuke Hiranuma, Takuma Shibata, Ryutaro Fukui, Yuji Motoi, Yusuke Murakami, et al. "The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages." International Immunology 32, no. 12 (August 25, 2020): 785–98. http://dx.doi.org/10.1093/intimm/dxaa055.
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Abstract Toll-like receptors (TLRs) impact myeloid cell responsiveness to environmental cues such as pathogen components and metabolites. Although TLR protein expression in monocytes and tissue macrophages is thought to be optimized for microenvironments in each tissue, a comprehensive study has not been reported. We here examined protein expression of endogenous TLRs in tissue-resident myeloid cells. Neutrophils in peripheral blood, spleen, liver and lung expressed TLR2, TLR4 and TLR5 in all tissues. Ly6C+ MHC II‒ classical monocytes mature into Ly6C‒ MHC II+ monocyte-derived dendritic cells (moDCs) or Ly6C‒ MHC II‒ patrolling monocytes. These subsets were found in all the tissues studied. TLR2 and TLR4 were displayed on all of these subsets, regardless of location. In contrast, expression of endosomal TLRs did vary with tissues and subsets. moDCs expressed TLR9, but much less TLR7. In contrast, TLR7, not TLR3 or TLR9, was highly expressed in classical and patrolling monocytes. Tissue macrophages such as red pulp macrophages in the spleen, Kupffer cells in the liver, microglia in the brain, alveolar macrophages in the lung and adipose tissue macrophages all expressed TLR2, TLR4 and TLR3. TLR7 was also expressed in these tissue macrophages except Kupffer cells in the liver. TLR9 expression in tissue macrophages was much lower or hard to detect. These results suggest that expression of endosomal TLRs in myeloid cells is influenced by their differentiation status and tissue-specific microenvironments.
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Luchner, Marina, Sören Reinke, and Anita Milicic. "TLR Agonists as Vaccine Adjuvants Targeting Cancer and Infectious Diseases." Pharmaceutics 13, no. 2 (January 22, 2021): 142. http://dx.doi.org/10.3390/pharmaceutics13020142.
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Modern vaccines have largely shifted from using whole, killed or attenuated pathogens to being based on subunit components. Since this diminishes immunogenicity, vaccine adjuvants that enhance the immune response to purified antigens are critically needed. Further advantages of adjuvants include dose sparing, increased vaccine efficacy in immunocompromised individuals and the potential to protect against highly variable pathogens by broadening the immune response. Due to their ability to link the innate with the adaptive immune response, Toll-like receptor (TLR) agonists are highly promising as adjuvants in vaccines against life-threatening and complex diseases such as cancer, AIDS and malaria. TLRs are transmembrane receptors, which are predominantly expressed by innate immune cells. They can be classified into cell surface (TLR1, TLR2, TLR4, TLR5, TLR6) and intracellular TLRs (TLR3, TLR7, TLR8, TLR9), expressed on endosomal membranes. Besides a transmembrane domain, each TLR possesses a leucine-rich repeat (LRR) segment that mediates PAMP/DAMP recognition and a TIR domain that delivers the downstream signal transduction and initiates an inflammatory response. Thus, TLRs are excellent targets for adjuvants to provide a “danger” signal to induce an effective immune response that leads to long-lasting protection. The present review will elaborate on applications of TLR ligands as vaccine adjuvants and immunotherapeutic agents, with a focus on clinically relevant adjuvants.
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Patra, Mahesh Chandra, Asma Achek, Gi-Young Kim, Suresh Panneerselvam, Hyeon-Jun Shin, Wook-Yong Baek, Wang Hee Lee, et al. "A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models." Cells 9, no. 7 (July 9, 2020): 1648. http://dx.doi.org/10.3390/cells9071648.
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Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE.
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Hung, Yun-Fen, Chiung-Ya Chen, Yi-Chun Shih, Hsin-Yu Liu, Chiao-Ming Huang, and Yi-Ping Hsueh. "Endosomal TLR3, TLR7, and TLR8 control neuronal morphology through different transcriptional programs." Journal of Cell Biology 217, no. 8 (May 18, 2018): 2727–42. http://dx.doi.org/10.1083/jcb.201712113.
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Neuroinflammation is associated with diverse neurological disorders. Endosomal Toll-like receptors (TLRs) including TLR3, TLR7, and TLR8 cell-autonomously regulate neuronal differentiation. However, the mechanisms by which these three TLRs affect neuronal morphology are unclear. In this study, we compare these TLRs in mouse neurons. By combining in vitro neuronal cultures, in utero electroporation, and transcriptomic profiling, we show that TLR8, TLR7, and TLR3 promote dendritic pruning via MYD88 signaling. However, they induce different transcriptomic profiles related to innate immunity, signaling, and neuronal development. The temporal expression patterns and the effects on neuronal morphology are not identical upon activation of these endosomal TLRs. Pathway analyses and in vitro studies specifically implicate mitogen-activated protein kinase signaling in TLR8-mediated dendritic pruning. We further show that TLR8 is more critical for dendritic arborization at a late development stage in vivo. The activation of TLR8, TLR7, or TLR3 results in dendritic shortening, and TLR7 and TLR3 but not TLR8 also control axonal growth. In-depth transcriptomic analyses show that TLRs use different downstream pathways to control neuronal morphology, which may contribute to neuronal development and pathological responses.
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Veneziani, Irene, Claudia Alicata, Andrea Pelosi, Nadine Landolina, Biancamaria Ricci, Valentina D'Oria, Anna Fagotti, Giovanni Scambia, Lorenzo Moretta, and Enrico Maggi. "Toll-like receptor 8 agonists improve NK-cell function primarily targeting CD56brightCD16− subset." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003385. http://dx.doi.org/10.1136/jitc-2021-003385.
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BackgroundToll-like receptors (TLRs) are pattern-recognition sensors mainly expressed in innate immune cells that directly recognize conserved pathogen structures (pathogen-associated molecular patterns-PAMPs). Natural killer (NK) cells have been described to express different endosomal TLRs triggered by RNA and DNA sequences derived from both viruses and bacteria. This study was addressed to establish which endosomal TLR could directly mediate NK activation and function after proper stimuli. It was also important to establish the most suitable TLR agonist to be used as adjuvant in tumor vaccines or in combined cancer immunotherapies.MethodsWe assessed endosomal TLR expression in total NK cells by using RT-qPCR and western blotting technique. In some experiments, we purified CD56brightCD16− and CD56dimCD16+ cells subsets by using NK Cell Isolation Kit Activation marker, cytokine production, CD107a expression and cytotoxicity assay were evaluated by flow cytometry. Cytokine release was quantified by ELISA. NK cells obtained from ovarian ascites underwent the same analyses.ResultsAlthough the four endosomal TLRs (TLR3, TLR7/8, and TLR9) were uniformly expressed on CD56brightCD16− and CD56dimCD16+ cell subsets, the TLR7/8 (R848), TLR3 (polyinosinic-polycytidylic acid, Poly I:C) and TLR9 (ODN2395) ligands promoted NK-cell function only in the presence of suboptimal doses of cytokines, including interleukin (IL)-2, IL-12, IL-15, and IL-18, produced in vivo by other environmental cells. We showed that R848 rather than TLR3 and TLR9 agonists primarily activated CD56brightCD16− NK cells by increasing their proliferation, cytokine production and cytotoxic activity. Moreover, we demonstrated that R848, which usually triggers TLR7 and TLR8 on dendritic cells, macrophages and neutrophils cells, activated CD56brightCD16− NK-cell subset only via TLR8. Indeed, specific TLR8 but not TLR7 agonists increased cytokine production and cytotoxic activity of CD56brightCD16− NK cells. Importantly, these activities were also observed in peritoneal NK cells from patients with metastatic ovarian carcinoma, prevalently belonging to the CD56brightCD16− subset.ConclusionThese data highlight the potential value of TLR8 in NK cells as a new target for immunotherapy in patients with cancer.
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Gallego, Carolina, Douglas Golenbock, Maria Adelaida Gomez, and Nancy Gore Saravia. "Toll-Like Receptors Participate in Macrophage Activation and Intracellular Control of Leishmania (Viannia) panamensis." Infection and Immunity 79, no. 7 (April 25, 2011): 2871–79. http://dx.doi.org/10.1128/iai.01388-10.
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ABSTRACTToll-like receptors (TLRs) play a central role in macrophage activation and control of parasitic infections. Their contribution to the outcome ofLeishmaniainfection is just beginning to be deciphered. We examined the interaction ofLeishmania panamensiswith TLRs in the activation of host macrophages.L. panamensisinfection resulted in upregulation of TLR1, TLR2, TLR3, and TLR4 expression and induced tumor necrosis factor alpha (TNF-α) secretion by human primary macrophages at comparable levels and kinetics to those of specific TLR ligands. The TLR dependence of the host cell response was substantiated by the absence of TNF-α production in MyD88/TRIF−/−murine bone marrow-derived macrophages and mouse macrophage cell lines in response to promastigotes and amastigotes. Systematic screening of TLR-deficient macrophages revealed that TNF-α production was completely abrogated in TLR4−/−macrophages, consistent with the increased intracellular parasite survival at early time points of infection. TNF-α secretion was significantly reduced in macrophages lacking endosomal TLRs but was unaltered by a lack of TLR2 or MD-2. Together, these findings support the participation of TLR4 and endosomal TLRs in the activation of host macrophages byL. panamensisand in the early control of infection.
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Mandraju, Rajakumar, Sean Murray, James Forman, and Chandrashekhar Pasare. "Differential regulation of CD8 T cell responses by surface and endosomal TLRs (INC6P.347)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 121.14. http://dx.doi.org/10.4049/jimmunol.192.supp.121.14.
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Abstract Sensing of pathogen/pathogen derived products through Toll like receptors (TLRs) induces dendritic cell (DC) maturation characterized by the expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. These two signals play a critical role in activation and differentiation of CD4 T cells. However, since the role of TLRs in the regulation of CD8 T cell responses is not clear we sought to address their role in this process. Our results show that although most TLRs induce the CD8 T cell proliferation in-vitro, there are significant differences in the CD8 T cell priming in-vivo to pathogenic infections. Endosomal TLRs (TLR3 and TLR9) that sense nucleic acids show a remarkable ability to induce CD8 T cell responses. However, surface TLRs (TLR2 and TLR4) that sense bacterial ligands were incapable of inducing CD8 T cell responses. Moreover, surface TLRs dominantly suppress the CD8 T cell activation induced by endosomal TLRs. Cell migration experiments show that surface TLR activation skewed lymphoid (CD11c+, CD8+) to myeloid (CD11c+, CD11b+ CD8-) DC populations in the draining lymph nodes. We also found that DC intrinsic TLR2 and TLR4, acting in a MyD88-dependent manner, altered the ability of DCs to prime CD8 T cells. In summary, our results demonstrate that bacterial co-infection dampens the ability of DCs to induce efficient anti-viral CD8 T cell responses.
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McAlpine, William, Lei Sun, Kuan-wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang, et al. "Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function." Proceedings of the National Academy of Sciences 115, no. 49 (November 15, 2018): E11523—E11531. http://dx.doi.org/10.1073/pnas.1814753115.
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The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8−/− macrophages. Smcr8−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.
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Averett, D. R., S. P. Fletcher, W. Li, S. E. Webber, and J. R. Appleman. "The pharmacology of endosomal TLR agonists in viral disease." Biochemical Society Transactions 35, no. 6 (November 23, 2007): 1468–72. http://dx.doi.org/10.1042/bst0351468.
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The discovery of endosomal TLRs (Toll-like receptors) and their natural ligands has accelerated efforts to exploit them for therapeutic benefit. Importantly, this was preceded by clinical exploration of agents now known to be endosomal TLR agonists. Clinical effects in viral disease have been reported with agonists of TLR3, TLR7, TLR7/8 and TLR9, and the TLR7 agonist imiquimod is marketed for topical use against warts, a papillomavirus disease. The observed pre-clinical and clinical profiles of agonists of each of these TLRs suggest induction of a multifaceted innate immune response, with biomarker signatures indicative of type 1 interferon induction. However, these agents differ in both their pharmaceutical characteristics and the cellular distribution of their target TLRs, suggesting that drugs directed to these targets will display differences in their overall pharmacological profiles.
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Ohto, Umeharu, Hiromi Tanji, Takuma Shibata, Elena Krayukhina, Susumu Uchiyama, Kensuke Miyake, and Toshiyuki Shimizu. "Structural studies of nucleic acid sensing Toll-like receptor." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C252. http://dx.doi.org/10.1107/s2053273314097472.
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Toll-like receptors (TLRs) sense pathogen-associated molecular patterns originating from invading microorganism and evoke innate immune responses. Among TLRs, TLR3, TLR7, TLR8, and TLR9 are localized to endosomal membranes and are responsible for the recognition of nucleic acids. TLR7 and TLR8 recognize single stranded RNA. In addition, TLR7 and TLR8 are activated by small chemical compounds. TLR9 recognizes DNA containing Cytosine-phosphate-Guanine motif. Theses nucleic acid sensing TLRs are attractive therapeutic targets for the modulation of immune responses in the viral and bacterial infections and in the pathogenesis of autoimmune diseases. However, the structural basis for the nucleic acid recognition and signaling mechanisms remains to be elucidated. Therefore, we conducted crystallographic studies of these TLRs. Recently, we have determined the crystal structures of the extracellular domain of human TLR8 in the unliganded form and in the liganded forms with chemical ligands (Tanji et al., 2013). Both unliganded and liganded forms of TLR8 were dimer. Ligands were located at two equivalent positions in the dimerization interface. The ligand binding induced the reorganization of the preformed dimer to the activated dimer such that the C-terminal regions of the two protomers are in close proximity to enable the subsequent dimerization of the intracellular signaling domains and its interactions with adaptor proteins.
Dissertations / Theses on the topic "Endosomal TLRs"
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CAPPELLETTI, CRISTINA. "Type I interferons and toll-like receptors are linked to pathological alterations of idiopathic inflammatory myopathiens." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2009. http://hdl.handle.net/10281/9235.
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Objective: The triggering factor of inflammation in idiopathic inflammatory myopathies (IIMs) is
still unknown and an involvement of viruses or bacteria has been put forward. We sought to
investigate the expression of type I interferons (IFNα/β) and of endosomal Toll-like receptors
(TLRs) in IIM muscles.
Methods: Ten IIM and 5 control muscle biopsies were assessed by microarray analysis for the
expression of approximately 16,000 genes; 37 additional samples from IIM and controls were
studied for IFNα/β-dependent genes and intracellular TLR expression using
immunohistochemistry, confocal miscroscopy, real-time quantitative and qualitative PCR.
Results: IFNα/β-dependent gene transcripts were up-regulated in all IIM muscle specimens
compared to controls. In juvenile dermatomyositis (JDM) ISG15 (408-fold), IFIT3 (261-fold), MX1
(99-fold), IRF7 (37-fold) were those most expressed. TLR3, TLR7 and TLR9 were differentially
expressed in IIM muscles: TLR3 was highly up-regulated in JDM, localized on vascular endothelial
cells, muscle infiltrating cells and regenerating myofibers; TLR7 and TLR9 were frequently
detected in polymyositis (PM), mainly on cell infiltrates (particularly plasma cells), and on some
injured myofibers.
Conclusion: Transcriptome analysis indicated that IFNα/β-induced molecules play a key role in the
pathogenesis of IIMs, particularly in JDM. Endosomal TLRs represent important effector molecules
that link innate and adaptive immune responses in affected muscles, showing their potential as new
therapeutic targets for the IIM treatment.
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Combes, Alexis. "Caractérisation du rôle de BAD-LAMP comme chaperonne des "Toll like receptors" au sein des cellules dendritiques plasmacytoïdes humaines." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4057.
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Les cellules dendritiques plasmacytoïdes humaines (pDCs) ont été montrées comme les principales cellules productrices d'interférons de type I (IFN) suivant une stimulation de leurs récepteurs TLRs intracellulaires. Après activation, les pDCs contrôlent la localisation subcellulaire de ces TLRs menant à une production séquentielle de cytokines. Une première vague d’IFN due la voie IRF dans les endosomes précoces, suivi de la production des cytokines pro-inflammatoires due à la voie NfκB dans les endosomes tardifs. BAD-LAMP/LAMP5, membre de la famille des protéines LAMP, spécifique du cerveau chez la souris est également exprimée par les pDCs humaines. Nous révélons ici le rôle de BAD-LAMP dans la régulation du transport de TLR9 dans les pDCs. Suite à une stimulation par CpG, BAD-LAMP et TLR9 atteignent des endosomes spécialisés dans la signalisation IRF VAMP3+. Le blocage de BAD-LAMP altère le transport intracellulaire de TLR9 par sa rétention dans les endosomes VAMP3+. Alors que l’expression ectopique de BAD-LAMP accélère le transport de TLR9 dans les lysosomes LAMP1+. La rétention dans les compartiments VAMP3+ impact directement la signalisation TLR9, en augmentant la production IFN et en diminuant celle du TNFα. De plus, nous avons démontré que BAD-LAMP est régulée négativement par l’IFN. A l’inverse, les pDCs traitées avec des surnageants tumoraux ainsi que les pDCs infiltrant les tumeurs mammaires présentent à la fois un défaut dans la production d'IFN et un maintien de l’expression de BAD-LAMP. BAD-LAMP est donc un régulateur essentiel du transport de TLR9 dans les pDCs humaines qui traduit l’efficacité de la signalisation TLR9 dans des conditions pathologiquesHuman plasmacytoïd dendritic cells (pDCs) have been shown to be the principal producer of type-I interferons (IFNs) following intracellular TLRs stimulation. Upon activation, pDCs tightly control TLRs sub-cellular localization in specialized endosomes, leading to sequential programs of cytokines production: a first rapid wave of type-I IFN, due to IRF signalling from early endosomes, followed by pro-inflammatory cytokines production, dependent on NfκB signalling from late endosomal compartments. BAD-LAMP/LAMP5, an atypical member of the LAMP protein family, is brain specific in mice. In Human, BAD-LAMP is also expressed in pDCs. We reveal here a novel step of TLR regulation mediated by BAD-LAMP, that controls TLR9 access to, and signalling from, specialized subsets of endosomes in human pDCs. Upon CpG stimulation, BAD-LAMP and TLR9 follow a common endocytic sorting step, in order to reach early, IRF-signalling, VAMP3+ endosomes. BAD-LAMP silencing alters TLR9 traffic and promotes its retention in VAMP3+ endosomes, while ectopic BAD-LAMP expression triggers accelerated TLR9 transport to LAMP1+ lysosomes. Retention in VAMP3+ endosomes impacts directly on TLR9 signalling by increasing IFN production and decreasing TNFα. Importantly, we found that BAD-LAMP expression is down-regulated by IFN exposure. Conversely, pDCs treated with tumour supernatants or pDCs infiltrating human breast tumors, present both sustained BAD-LAMP expression, and defect in IFN production. BAD-LAMP is therefore an essential regulator of TLR9 transport in human pDCs and a marker of TLR9 signalling efficiency under pathological conditions
Conference papers on the topic "Endosomal TLRs"
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Han, Xinbing, Xin Li, Medhavi Bole, Asha Anandiah, Sharon Zhou, Benjamin Nelson, Naimish R. Patel, Henry Koziel, and Souvenir D. Tachado. "Human Macrophages Recognize HIV SSRNA Through Endosomal TLR8." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6252.
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