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1
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.
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Lai, Chao-Yang, Yu-Wen Su, Kuo-I. Lin, Li-Chung Hsu, and Tsung-Hsien Chuang. "Natural Modulators of Endosomal Toll-Like Receptor-Mediated Psoriatic Skin Inflammation." Journal of Immunology Research 2017 (2017): 1–15. http://dx.doi.org/10.1155/2017/7807313.
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Psoriasis is a chronic inflammatory autoimmune disease that can be initiated by excessive activation of endosomal toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. Therefore, inhibitors of endosomal TLR activation are being investigated for their ability to treat this disease. The currently approved biological drugs adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, and secukizumab are antibodies against effector cytokines that participate in the initiation and development of psoriasis. Several immune modulatory oligonucleotides and small molecular weight compounds, including IMO-3100, IMO-8400, and CPG-52364, that block the interaction between endosomal TLRs and their ligands are under clinical investigation for their effectiveness in the treatment of psoriasis. In addition, several chemical compounds, including AS-2444697, PF-05387252, PF-05388169, PF-06650833, ML120B, and PHA-408, can inhibit TLR signaling. Although these compounds have demonstrated anti-inflammatory activity in animal models, their therapeutic potential for the treatment of psoriasis has not yet been tested. Recent studies demonstrated that natural compounds derived from plants, fungi, and bacteria, including mustard seed, Antrodia cinnamomea extract, curcumin, resveratrol, thiostrepton, azithromycin, and andrographolide, inhibited psoriasis-like inflammation induced by the TLR7 agonist imiquimod in animal models. These natural modulators employ different mechanisms to inhibit endosomal TLR activation and are administered via different routes. Therefore, they represent candidate psoriasis drugs and might lead to the development of new treatment options.
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Baumann, Christoph L., Irene M. Aspalter, Omar Sharif, Andreas Pichlmair, Stephan Blüml, Florian Grebien, Manuela Bruckner, et al. "CD14 is a coreceptor of Toll-like receptors 7 and 9." Journal of Experimental Medicine 207, no. 12 (November 15, 2010): 2689–701. http://dx.doi.org/10.1084/jem.20101111.
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Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid–mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.
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Mielcarska, Matylda Barbara, Magdalena Bossowska-Nowicka, Karolina Paulina Gregorczyk, Zbigniew Wyzewski, and Felix Ngosa Toka. "Tyrosine kinase Syk interacts with Hrs after TLR3 stimulation in murine microglial cells." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 129.17. http://dx.doi.org/10.4049/jimmunol.198.supp.129.17.
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Abstract TLR3 (Toll-like receptor 3) belongs to the family of receptors involved in innate immune response. Present in endosomal compartment in cells, TLR3 recognizes the dsRNA (double-stranded RNA), viral nucleic acid or intermediate during viral replication and initiates signal transduction leading to inflammatory response. However, the first steps of signaling cascade occurring in cells immediately after TLR3 stimulation are still not well understood and require careful attention. In this paper we demonstrate that after poly(I:C) (dsRNA mimetic) stimulation of murine microglial cells (C8D1A cell line) tyrosine kinase Syk interacts with Hrs (hepatocyte growth factor regulated tyrosine kinase substrate), one of the ESCRT-0 (endosomal sorting complex required for transportation-0) components. This protein complex was recently implicated in trafficking of other endosomal TLRs, TLR7 and TLR9, and plays a possible role in the TLR3 signaling. Phosphorylation of Hrs, which is a very likely result of Hrs-Syk interaction, also takes place after poly(I:C) stimulation, strongly suggesting that an association between activated TLR3 and ESCRT-0 exists. Therefore, Hrs may influence TLR3 signaling pathways, but this requires further investigation.
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Veneziani, Irene, Claudia Alicata, Lorenzo Moretta, and Enrico Maggi. "The Latest Approach of Immunotherapy with Endosomal TLR Agonists Improving NK Cell Function: An Overview." Biomedicines 11, no. 1 (December 27, 2022): 64. http://dx.doi.org/10.3390/biomedicines11010064.
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Toll-like receptors (TLRs) are the most well-defined pattern recognition receptors (PRR) of several cell types recognizing pathogens and triggering innate immunity. TLRs are also expressed on tumor cells and tumor microenvironment (TME) cells, including natural killer (NK) cells. Cell surface TLRs primarily recognize extracellular ligands from bacteria and fungi, while endosomal TLRs recognize microbial DNA or RNA. TLR engagement activates intracellular pathways leading to the activation of transcription factors regulating gene expression of several inflammatory molecules. Endosomal TLR agonists may be considered as new immunotherapeutic adjuvants for dendritic cell (DC) vaccines able to improve anti-tumor immunity and cancer patient outcomes. The literature suggests that endosomal TLR agonists modify TME on murine models and human cancer (clinical trials), providing evidence that locally infused endosomal TLR agonists may delay tumor growth and induce tumor regression. Recently, our group demonstrated that CD56bright NK cell subset is selectively responsive to TLR8 engagement. Thus, TLR8 agonists (loaded or not to nanoparticles or other carriers) can be considered a novel strategy able to promote anti-tumor immunity. TLR8 agonists can be used to activate and expand in vitro circulating or intra-tumoral NK cells to be adoptively transferred into patients.
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Wang, Kuan-wen, Xiaoming Zhan, William McAlpine, Zhao Zhang, Jin Huk Choi, Hexin Shi, Takuma Misawa, et al. "Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice." Proceedings of the National Academy of Sciences 116, no. 23 (May 16, 2019): 11380–89. http://dx.doi.org/10.1073/pnas.1901407116.
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LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen forN-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations inLrba. Although Tregcells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice.Lrba−/−DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout ofUnc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.
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Skert, Cristina, Manuela Fogli, Simone Perucca, Simona Fiorentini, Emirena Garrafa, Carla Filì, Chiara Colombi, et al. "Betaherpesvirus Reactivation and Toll-Like Receptor Expression After Allogeneic Stem Cell Transplantation." Blood 118, no. 21 (November 18, 2011): 4924. http://dx.doi.org/10.1182/blood.v118.21.4924.4924.
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Abstract Abstract 4924 Introduction. β-herpesviruses, such as CMV and HHV6, are important pathogen in transplanted patients. The morbidity because of CMV reactivation after allogeneic stem cell transplantation (SCT) has led to the monitoring of this virus and to introduction of preemptive therapy. However, CMV infection is still one of the most challenging complications, because CMV disease may occur as life-threatening pneumonitis, and may increase the risk of opportunistic infections. HHV6 reactivation has been demonstrated after SCT and this virus is recognized as important pathogen, either by direct infection or via interaction with CMV. Innate and adaptive immune response against these viruses involves the activation of Toll-like receptors (TLRs). TLRs belong to type I transmembrane glycoprotein receptor family and recognize pathogen-associated molecular patterns (PAMPs). Viral nucleic acids and viral structural proteins, such as glycoproteins, are considered as PAMPs. Endosomal TLRs (TLR3, 7, 8 and 9) recognize viral nucleic acids and some surface TLRs may be involved in the detection of structural proteins. Some clinical and experimental evidences indicate that CMV and HHV-6 can modulate the immune system and influence the immune reconstitution after SCT. However, the role of TLRs in this complex interplay remains unclear, especially in the setting of allogeneic SCT. The aim of this study was to evaluate the expression of TLRs on lymphocytes and monocytes in relation to CMV and HHV6 reactivation in the early period after allogeneic SCT. Methods. CMV and HHV6 reactivation was monitored weekly by quantitative real-time PCR until the second month after SCT. The expression of TLRs on lymphocytes and monocytes was analysed by flow cytometry as mean fluorescence intensity at day +30 and in any case before CMV or HHV6 reactivation. 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. CMV reactivation within 2 months after transplantation was observed in 13 out of 33 patients. CMV pneumonitis was observed in 1 patient. HHV-6 reactivation was detected in 1 patient. Median age was 45 years (range, 22–64) and 21 patients were male. TLRs expression and function did not significantly differ in controls and patients without CMV. Lymphocytes of patients with CMV reactivation showed an increased expression of TLR5 (4,1±2,4 vs 2,0±1,7 p=0,008). TLR8 expression was lower on monocytes with CMV reactivation (0,8±0,9 vs 2,0±1,7 p=0,03). MCP-1 relative induction post-stimulation of TLR1 and 8 was significantly decreased in patients with CMV reactivation (p<0,04). Conclusions. Surface TLR2 and intracellular TLR3 and 9 are reported to recognize CMV by some authors. In our study, surface TLR5 and intracellular TLR8 seem to be involved in the interaction between CMV and the immune system of transplanted patients. In particular, TLR8 could play a protective role. MCP-1 production upon TLR1 and 8 activation negatively correlates with CMV reactivation. The defective immune system after SCT could explain these results, which could be confirmed by the assessment of a larger number of patients and the analysis of other possible interfering factors. Disclosures: No relevant conflicts of interest to declare.
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Nelson, Alexander J., and Yee Ling WU. "Toll-like receptor signaling directly modulates B cell antibody responses." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 151.28. http://dx.doi.org/10.4049/jimmunol.204.supp.151.28.
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Abstract Toll-like receptor (TLR) signaling alone or in concert with other cellular or molecular signals helps shape responses by different cell types. Murine B lymphocytes express cell surface-bound TLRs 1, 2, 4, 6 and endosomal TLRs 3, 7, 9. This study aims to delineate the effects of these TLRs on B cell responses including proliferation, activation and antibody class-switch recombination (CSR). We stimulated mature, naïve B cells in vitro with individual TLR agonists alone or together with T cell help (via ligation of CD40) and the TH2 cytokine interleukin-4 (IL-4). We measured proliferation by CellTrace Violet assay, cell activation by surface expression of B cell activation markers, and analyzed antibody class switching by surface expression and secreted levels of antibody isotypes by flow cytometry. We found that in the presence of a minimal level of anti-CD40, stimulation with TLRs 1/2, 2/6, 4, and 9 agonists induced cell proliferation and up-regulation of activation markers including CD69 and CD80. While both types of TLR agonists down-regulated class switching to IgG1, stimulation of the surface-bound TLRs (1/2, 2/6 and 4) increased class switching to IgG3 and IgG2b. In contrast, stimulation of endosomal TLR9 inhibited switching to all isotypes. The addition of IL-4 induced robust cell proliferation and class switching to IgG1, and TLR 1/2, 2/6, 4, and 9 agonists further enhanced these IL-4-mediated B cell responses. Altogether, our data demonstrate differential effects of surface bound and endosomal TLRs on B cell responses. Activation of surface-bound TLRs, but not endosomal TLR9, triggers CSR to TH1-associated antibody isotypes, while both groups of TLRs synergize the effect of IL-4 on driving CSR to IgG1.
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Minton, Kirsty. "Regulation of endosomal TLRs." Nature Reviews Immunology 19, no. 11 (September 27, 2019): 660–61. http://dx.doi.org/10.1038/s41577-019-0229-1.
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Wang, James Q., Bruce Beutler, Christopher C. Goodnow, and Keisuke Horikawa. "Inhibiting TLR9 and other UNC93B1-dependent TLRs paradoxically increases accumulation of MYD88L265P plasmablasts in vivo." Blood 128, no. 12 (September 22, 2016): 1604–8. http://dx.doi.org/10.1182/blood-2016-03-708065.
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Key Points Inhibiting endosomal TLRs suppresses MYD88L265P B-cell proliferation in vitro. Inhibition of endosomal TLRs paradoxically enhances accumulation of MYD88L265P B cells as plasmablasts in vivo.
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Ganguly, Dipyaman, Georgios Chamilos, Roberto Lande, Josh Gregorio, Stephan Meller, Valeria Facchinetti, Bernhard Homey, Franck J. Barrat, Tomasz Zal, and Michel Gilliet. "Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8." Journal of Experimental Medicine 206, no. 9 (August 24, 2009): 1983–94. http://dx.doi.org/10.1084/jem.20090480.
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Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid–recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA–LL37 complexes activate TLR7 and, like self-DNA–LL37 complexes, trigger the secretion of IFN-α without inducing maturation or the production of IL-6 and TNF-α. In contrast to self-DNA–LL37 complexes, self-RNA–LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-α and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA–LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.
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Ao, Da, Xueliang Liu, Sen Jiang, Yulin Xu, Wanglong Zheng, Nanhua Chen, François Meurens, and Jianzhong Zhu. "The Signal Peptide and Chaperone UNC93B1 Both Influence TLR8 Ectodomain Intracellular Endosomal Localization." Vaccines 10, no. 1 (December 23, 2021): 14. http://dx.doi.org/10.3390/vaccines10010014.
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Toll-like receptor 8 (TLR8) is a single-stranded RNA sensing receptor and is localized in the cellular compartments, where it encounters foreign or self-nucleic acids and activates innate and adaptive immune responses. However, the mechanism controlling intracellular localization TLR8 is not completely resolved. We previously revealed the intracellular localization of TLR8 ectodomain (ECD), and in this study, we investigated the mechanism of the intracellular localization. Here we found that TLR8 ECDs from different species as well as ECDs from different TLRs are all intracellularly localized, similarly to the full-length porcine TLR8. Furthermore, porcine, bovine, and human TLR8 ECDs are all localized in cell endosomes, reflecting the cellular localization of TLR8. Intriguingly, none of post-translational modifications at single sites, including glycosylation, phosphorylation, ubiquitination, acetylation, and palmitoylation alter porcine TLR8-ECD endosomal localization. Nevertheless, the signal peptide of porcine TLR8-ECD determines its endosomal localization. On the other hand, signaling regulator UNC93B1 also decides the endosomal localization of porcine, bovine, and human TLR8 ECDs. The results from this study shed light on the mechanisms of not only TLR8 intracellular localization but also the TLR immune signaling.
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Lai, Chao-Yang, Da-Wei Yeh, Chih-Hao Lu, Yi-Ling Liu, Li-Rung Huang, Cheng-Yuan Kao, Huan-Yuan Chen, et al. "Thiostrepton inhibits psoriasis-like inflammation induced by TLR7, TLR8, and TLR9." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.41. http://dx.doi.org/10.4049/jimmunol.196.supp.124.41.
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Abstract Toll-like receptors 7, 8 and 9 (TLR7-9) comprise a subfamily of TLR. Activation of these TLRs has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. Thus antagonists of these TLRs are being investigated for their therapeutic applications on these diseases. Bortezomib is a proteasome inhibitor known to suppress activation of these TLRs. This drug is approved for the treatment of multiple myeloma, and its inhibitory effects on autoimmune disorders such as psoriasis, RA, and SLE have also been investigated in animal models. In an attempt to develop novel TLR7-9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles in cells treated with bortezomib. These profiles were then used as an input to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. Here we report that the antibiotic thiostrepton is a novel TLR7–9 inhibitor. Like bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and dendritic cells. In contrast to bortezomib, thiostrepton is less cytotoxic to dendritic cells, and its inhibitory activity is more specific to TLR7–9. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms. One mechanism is similar to the proteasome inhibitory function of bortezomib, and the other is through inhibition of endosomal acidification. In different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel and specific inhibitor to TLR7–9.
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Elshikha, Ahmed Samir, Georges Abboud, Laurence Morel, and Sihong Song. "Targeting proteolytic cleavage of Toll-Like receptors by alpha-1 antitrypsin inhibited dendritic cells activation and function." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 60.20. http://dx.doi.org/10.4049/jimmunol.208.supp.60.20.
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Abstract Toll-like receptors (TLRs) on dendritic cells (DC) interact with self-antigens and play a critical role in systemic lupus erythematosus (SLE) pathogenesis. TLR3, TLR7/8, or TLR9 are endosomal receptors that require proteolytic processing in the endolysosome to initiate signaling in response to DNA, single-stranded RNA, and double-stranded RNA. Targeting this proteolytic processing may represent a novel strategy for inhibiting TLR mediated pathogenesis. Human alpha 1 antitrypsin (hAAT) is a protease inhibitor with anti-inflammatory and immunoregulatory properties. However, the effect of hAAT on TLRs is not clear. In this study we first tested the effect of hAAT on DCs. We showed that hAAT treatment inhibited TLR7/8 and TLR9 agonists induced DC expressions of CD80, CD86 and MHC-II and significantly reduced the productions of IL-12, IFN-α and CXCL-10. Mechanistically, hAAT lowered the expression of interferon signature genes (MX-I, Isg-15, IRF-7, Il-12p40 and TNF-α). Importantly, western blot analysis showed that hAAT treatment reduced the active form (cleaved) of TLR9 in DCs indicating a novel mechanism of hAAT function in the immune system. Our in vivo studies in mouse models also showed that hAAT attenuated TLR agonist-induced pathogenesis. These data demonstrated that hAAT inhibited TLR7/8 and TLR9 signaling pathways in DCs, which are critical for lupus development. These findings not only advanced the current knowledge of hAAT biology, but also implied an insight for clinical application of hAAT.
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Meibers, Hannah, Margaret McDaniel, and Chandrashekhar Pasare. "Vps33B is a crucial regulator of Type I Interferon response downstream of the cGAS-STING pathway." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 68.13. http://dx.doi.org/10.4049/jimmunol.204.supp.68.13.
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Abstract Vacuolar protein sorting-associated protein 33B (Vps33B) plays a critical role in the trafficking of endosomal contents to lysosomes in macrophages, particularly following Toll-like receptor (TLR) activation. Upon activation by microbial ligands, TLRs are internalized into endosomes, then trafficked to lysosomes for degradation. We have previously shown that endosomal to lysosomal trafficking, and subsequent degradation of TLR4, is mediated by Vps33B. Without this crucial degradation step, TLRs remain trapped within altered endosomes, leading to an enhanced inflammatory response. Since Vps33B is critical for termination of signaling following TLR ligation, we wanted to determine if it had a conserved role in regulating other pattern recognition receptor (PRR) signaling pathways. Specifically, we investigated the role of Vps33B in regulating cytosolic DNA sensing by the cGAS-STING pathway. Absence of Vps33B in macrophages and mouse embryonic fibroblasts resulted in an exaggerated type 1 interferon and interferon-stimulated gene response after stimulation with dsDNA and other STING ligands. Our findings suggest that Vps33B has a conserved role as a regulator of innate inflammatory responses downstream of both plasma membrane as well as cytosolic PRRs. Mechanistically, we hypothesize that Vps33B plays a role in STING degradation, similarly to how it permits TLR4 degradation, through mediating endo-lysosomal trafficking. This would suggest a broad and critical role for Vps33B in PRR-induced vesicular transportation and receptor degradation. Future work will investigate the mechanisms by which Vps33B regulates STING-mediated signaling as well as its importance for anti-viral immunity.
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Russo, Carla, Ivan Cornella-Taracido, Luisa Galli-Stampino, Rishi Jain, Edmund Harrington, Yuko Isome, Simona Tavarini, et al. "Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells." Blood 117, no. 21 (May 26, 2011): 5683–91. http://dx.doi.org/10.1182/blood-2010-12-328138.
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Abstract TLR7 and TLR8 are intracellular sensors activated by single-stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 or TLR8 or both through an unknown mechanism. Notably, direct interaction between small molecules and TLR7 or TLR8 has never been shown. To shed light on how small molecule agonists target TLRs, we labeled 2 imidazoquinolines, resiquimod and imiquimod, and one adenine-based compound, SM360320, with 2 different fluorophores [5(6) carboxytetramethylrhodamine and Alexa Fluor 488] and monitored their intracellular localization in human plasmacytoid dendritic cells (pDCs). All fluorescent compounds induced the production of IFN-α, TNF-α, and IL-6 and the up-regulation of CD80 and CD86 by pDCs showing they retained TLR7-stimulating activity. Confocal imaging of pDCs showed that, similar to CpG-B, all compounds concentrated in the MHC class II loading compartment (MIIC), identified as lysosome-associated membrane protein 1+, CD63, and HLA-DR+ endosomes. Treatment of pDCs with bafilomycin A, an antagonist of the vacuolar-type proton ATPase controlling endosomal acidification, prevented the accumulation of small molecule TLR7 agonists, but not of CpG-B, in the MIIC. These results indicate that a pH-driven concentration of small molecule TLR7 agonists in the MIIC is required for pDC activation.
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Paradowska-Gorycka, Agnieszka, Anna Wajda, Barbara Stypińska, Ewa Walczuk, Marcela Walczyk, Anna Felis-Giemza, Jolanta Nałęcz-Janik, Aleksandra Poluch, and Marzena Olesińska. "The TLRs and IFNs in patients with connective tissue diseases." Postępy Polskiej Medycyny i Farmacji 7 (May 27, 2020): 1–10. http://dx.doi.org/10.5604/01.3001.0014.1583.
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Autoimmune connective tissue diseases (ACTD) are characterized by spontaneous stimulation of the immune system and the production of autoantibodies. Some autoantibodies may create an immune complex with DNA and/or RNA and promote tissue inflammation. Immune complexes that contain nucleic acids can act as ligands for endosomal Toll-like receptors (TLR), which activation induces secretion of the type I and type III interferons. The present study aimed to determine whether TLRs and IFNs genes could be considered as potential ACTD biomarkers. IFN-A and IFN-G showed a relationship with a predisposition to the development of SLE and MCTD, and IFN-B with a predisposition to the development of SLE. The TLR7 rs5743305 T allele and rs5743316 A allele may play a protective role against the development of MCTD, and the TLR7 rs1731479 T allele and TLR8 rs17256081 C allele may be predictors of MCTD development. mRNA expression of the IFN-α, IFN-β, IFN-γ, TLR3, TLR8 and TLR7 was significantly higher in patients with SLE compared to patients with MCTD and SSc. MCTD patients with anti-U1-70k (+) had higher IFN-γ and lower IFN-β serum levels than patients without this antibody. In patients with SLE, serum levels of IFN-α and IFN-γ correlate with the concentration of complement components, and serum levels of IFN-α with disease activity. The study confirmed that the TLR-IFN pathway may be considered as an important pathogenic mechanism for ACTD.
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Nahid, M., Lia Benso, John Shin, Huseyin Mehmet, Alexandra Hicks, and Ravisankar Ramadas. "Macrophage tolerance to MyD88-dependent TLR agonists is mediated by LPS-/R848-induced miR-146a (IRM12P.649)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 133.8. http://dx.doi.org/10.4049/jimmunol.194.supp.133.8.
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Abstract Toll like receptors (TLRs) TLRs facilitate the recognition of pathogens by immune cells and the initiation of the immune response, leading to the production of proinflammatory mediators. Production of proinflammatory mediators by innate immune cells such as macrophages is tightly regulated to facilitate pathogen clearance while limiting adverse impact on host tissue. Exposure to TLR ligands induces a state of temporary refractoriness to a subsequent exposure of a TLR ligand, a phenomenon referred to as ‘tolerance’. This study sought to evaluate the mechanistic regulation of TLR4 and TLR7/8 ligand induced tolerance to other TLRs by miR-146a. Using THP-1 macrophages as well as human M1 and M2 macrophages, we demonstrate that priming with a TLR4 agonist (LPS) or a TLR7/8 agonist (R848) induce tolerance to a panel of TLR ligands in macrophages, leading to the impaired production of a variety of cytokines and chemokines. We also demonstrate that overexpression of miR-146a is sufficient to mimic LPS- or R848-induced hyporesponsiveness. Conversely, the knockdown of miR-146a leads to LPS- or R848-induced TLR hyperresponsiveness. Furthermore, we demonstrate that while miR-146a dampens cytokine production following a primary stimulus with MyD88-dependent, but not MyD88- independent TLR pathways. Collectively, these data provide comprehensive evidence of the central role of miR-146a in TLR signaling tolerance to plasma membrane as well as endosomal TLR ligands in human macrophages.
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Pawar, Kamlesh, Megumi Shigematsu, Soroush Sharbati, and Yohei Kirino. "Infection-induced 5′-half molecules of tRNAHisGUG activate Toll-like receptor 7." PLOS Biology 18, no. 12 (December 17, 2020): e3000982. http://dx.doi.org/10.1371/journal.pbio.3000982.
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Toll-like receptors (TLRs) play a crucial role in the innate immune response. Although endosomal TLR7 recognizes single-stranded RNAs, their endogenous RNA ligands have not been fully explored. Here, we report 5′-tRNA half molecules as abundant activators of TLR7. Mycobacterial infection and accompanying surface TLR activation up-regulate the expression of 5′-tRNA half molecules in human monocyte-derived macrophages (HMDMs). The abundant accumulation of 5′-tRNA halves also occur in HMDM-secreted extracellular vehicles (EVs); the abundance of EV-5′-tRNAHisGUG half molecules is >200-fold higher than that of the most abundant EV-microRNA (miRNA). Sequence identification of the 5′-tRNA halves using cP-RNA-seq revealed abundant and selective packaging of specific 5′-tRNA half species into EVs. The EV-5′-tRNAHisGUG half was experimentally demonstrated to be delivered into endosomes in recipient cells and to activate endosomal TLR7. Up-regulation of the 5′-tRNA half molecules was also observed in the plasma of patients infected with Mycobacterium tuberculosis. These results unveil a novel tRNA-engaged pathway in the innate immune response and assign the role of “immune activators” to 5′-tRNA half molecules.
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Radovic-Moreno, Aleksandar F., Natalia Chernyak, Christopher C. Mader, Subbarao Nallagatla, Richard S. Kang, Liangliang Hao, David A. Walker, et al. "Immunomodulatory spherical nucleic acids." Proceedings of the National Academy of Sciences 112, no. 13 (March 16, 2015): 3892–97. http://dx.doi.org/10.1073/pnas.1502850112.
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Immunomodulatory nucleic acids have extraordinary promise for treating disease, yet clinical progress has been limited by a lack of tools to safely increase activity in patients. Immunomodulatory nucleic acids act by agonizing or antagonizing endosomal toll-like receptors (TLR3, TLR7/8, and TLR9), proteins involved in innate immune signaling. Immunomodulatory spherical nucleic acids (SNAs) that stimulate (immunostimulatory, IS-SNA) or regulate (immunoregulatory, IR-SNA) immunity by engaging TLRs have been designed, synthesized, and characterized. Compared with free oligonucleotides, IS-SNAs exhibit up to 80-fold increases in potency, 700-fold higher antibody titers, 400-fold higher cellular responses to a model antigen, and improved treatment of mice with lymphomas. IR-SNAs exhibit up to eightfold increases in potency and 30% greater reduction in fibrosis score in mice with nonalcoholic steatohepatitis (NASH). Given the clinical potential of SNAs due to their potency, defined chemical nature, and good tolerability, SNAs are attractive new modalities for developing immunotherapies.
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Leavy, Olive. "AP3 links endosomal TLRs and antigen presentation." Nature Reviews Immunology 12, no. 6 (May 18, 2012): 400. http://dx.doi.org/10.1038/nri3232.
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Leifer, Cynthia, James Brooks, Jody Cameron, and Gabriela Chiosis. "The Heat Shock Protein gp96 play a multifaceted role in regulating Toll-like receptor 9 (136.40)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 136.40. http://dx.doi.org/10.4049/jimmunol.184.supp.136.40.
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Abstract Inappropriate activation and failure to inactivate Toll-like receptors (TLRs) contribute to immune mediated pathology. Nucleic acid sensing TLRs, including TLR9, are tightly regulated to prevent self DNA and RNA recognition, which can contribute to autoimmune disease. The overall goal of our research is to determine the molecular mechanisms governing nucleic acid sensing TLRs using TLR9 as a model. Regulation of TLR9 includes control of intracellular trafficking by association with proteins such as the endoplasmic reticulum chaperone gp96. Obligate proteolytic cleavage of TLR9 to an 80 kDa form, p80, precedes TLR9 recognition of CpG DNA. Here we show that in the absence of gp96, there is a failure to generate p80. Furthermore, gp96 traffics with TLR9 to the endosomal compartment. Dissociation of gp96 from TLR9 using specific inhibitors leads to rapid degradation of the receptor and inhibition of signaling. CpG DNA pull down experiments demonstrate that gp96 is associated with the ligand-bound form of the receptor suggesting it contributes to CpG DNA recognition. We provide a model where gp96 plays a multifaceted role in TLR9 biology. These studies have major implications for pharmacologically manipulating the levels of active and inhibitory forms of TLR9 and other nucleic acid sensing TLRs, which will likely uncover novel therapeutic interventions for autoimmune diseases. AI076588 and AI076588-S1 (CAL).
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Park, Se-Ra, Dong-Jae Kim, Seung-Hyun Han, Min-Jung Kang, Jun-Young Lee, Yu-Jin Jeong, Sang-Jin Lee, et al. "Diverse Toll-Like Receptors Mediate Cytokine Production by Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans in Macrophages." Infection and Immunity 82, no. 5 (February 24, 2014): 1914–20. http://dx.doi.org/10.1128/iai.01226-13.
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ABSTRACTToll-like receptors (TLRs) orchestrate a repertoire of immune responses in macrophages against various pathogens.Fusobacterium nucleatumandAggregatibacter actinomycetemcomitansare two important periodontal pathogens. In the present study, we investigated TLR signaling regulating cytokine production of macrophages in response toF. nucleatumandA. actinomycetemcomitans. TLR2 and TLR4 are redundant in the production of cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]) inF. nucleatum- andA. actinomycetemcomitans-infected macrophages. The production of cytokines by macrophages in response toF. nucleatumandA. actinomycetemcomitansinfection was impaired in MyD88-deficient macrophages. Moreover, cytokine concentrations were lower in MyD88-deficient macrophages than in TLR2/TLR4 (TLR2/4) double-deficient cells. An endosomal TLR inhibitor, chloroquine, reduced cytokine production in TLR2/4-deficient macrophages in response toF. nucleatumandA. actinomycetemcomitans, and DNA fromF. nucleatumorA. actinomycetemcomitansinduced IL-6 production in bone marrow-derived macrophages (BMDMs), which was abolished by chloroquine. Western blot analysis revealed that TLR2/4 and MyD88 were required for optimal activation of NF-κB and mitogen-activated protein kinases (MAPKs) in macrophages in response toF. nucleatumandA. actinomycetemcomitans, with different kinetics. An inhibitor assay showed that NF-κB and all MAPKs (p38, extracellular signal-regulated kinase [ERK], and Jun N-terminal protein kinase [JNK]) mediateF. nucleatum-induced production of cytokines in macrophages, whereas NF-κB and p38, but not ERK and JNK, are involved inA. actinomycetemcomitans-mediated cytokine production. These findings suggest that multiple TLRs may participate in the cytokine production of macrophages against periodontal bacteria.
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Kiefer, Kerstin, Nathaniel Green, Michael Oropallo, Michael Cancro, and Ann Marshak-Rothstein. "BCR/TLR7 coligation uniquely drives plasma cell differentiation of autoreactive B cells (171.34)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.34. http://dx.doi.org/10.4049/jimmunol.188.supp.171.34.
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Abstract Endosomal Toll-like receptors (TLRs) play an important role in the manifestation of systemic autoimmune diseases such as SLE. In vitro, DNA-/RNA-associated autoantigens have been reported to activate B cells, pDCs, and other APCs, through TLR9/TLR7-dependent pathways. However, in vivo, TLR9 appears to negatively regulate TLR7-dependent responses. Hence, TLR9-/- autoimmune prone mice develop more severe disease and increased autoantibody titers against RNA associated proteins, while TLR7-/- and TLR7/9-/- autoimmune-prone mice develop less severe disease. AM14 BCR side-directed transgenic B cells recognize IgG2a-bound immune complexes (ICs) and initially proliferate in response to both DNA and RNA autoantigens. However, the TLR9-dependent DNA responses eventually promote a form of programmed cell death that can only be rescued by B cell survival factors such as BLyS. By contrast, the TLR7-dependent RNA responses promote differentiation to the plasma cell lineage. The RNA-driven phenotype is characterized by increased levels of plasma cell associated proteins such as IRF-4 and CD138 and antibody secretion. Even in the presence of BLyS, DNA containing ICs did not promote plasma cell development. Our results identify B cell intrinsic mechanisms whereby TLR9 activation restrains B cell responses and TLR7 activation induces a unique signal for plasma cell development.
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Lin, You-Sheng, Yung-Chi Chang, Ting-Yu Lai, Chih-Yuan Lee, Tsung-Hsien Chuang, and Li-Chung Hsu. "The role of novel E3 ubiquitin ligase in the regulation of TLR3 signaling pathway." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 226.26. http://dx.doi.org/10.4049/jimmunol.204.supp.226.26.
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Abstract Toll-like receptors (TLRs) are critical players in the host’s defense against infection by recognizing pathogen-associated molecular patterns (PAMPs) derived from microbes, and subsequently induce inflammatory responses, which eventually eliminate pathogens and repair damage tissues. However, excessive inflammation is detrimental to the host, and has been associated with the pathogenesis of various inflammatory and autoimmune diseases. Ubiquitination is a crucial strategy to alter protein function, expression, or cellular localization at the post-translational level, and has been shown to participate in the regulation of innate immune responses. We previously found that a novel E3 ubiquitin ligase was induced upon endosomal TLRs (TLR3/7/9) activation. In this project, we demonstrate that this E3 ubiquitin ligase negatively regulates TLR3-driven immune responses, which is dependent on its ubiquitin ligase activity. This novel E3 ubiquitin ligase controls TLR3 trafficking from the endosomes to the lysosomes for degradation. In addition, this E3 ubiquitin ligase interacts with TLR3 and promotes the ubiquitination of TLR3. We also found that lysosomal activity and intracellular pH value were altered in macrophages lacking this E3 ubiquitin ligase after poly(I:C) stimulation. Furthermore, we showed that mice with this E3 ubiquitin ligase deficiency were resistant to encephalomyocarditis virus (EMCV) infection due to enhanced type I interferon production. Our study together reveals this novel E3 ubiquitin ligase as a negative regulator of TLR3-induced inflammatory responses and proposes a novel mechanism for the termination of TLR3 signaling and immune response.
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Mukhopadhyay, Subhankar, Audrey Varin, Yunying Chen, Baoying Liu, Karl Tryggvason, and Siamon Gordon. "SR-A/MARCO–mediated ligand delivery enhances intracellular TLR and NLR function, but ligand scavenging from cell surface limits TLR4 response to pathogens." Blood 117, no. 4 (January 27, 2011): 1319–28. http://dx.doi.org/10.1182/blood-2010-03-276733.
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Abstract Phagocytic and pathogen sensing receptors are responsible for particle uptake and inflammation. It is unclear how these receptors' systems influence each other's function to shape an innate response. The class-A scavenger receptors SR-A (scavenger receptor A) and MARCO (macrophage receptor with collagenous structure) are 2 well-characterized phagocytic receptors that are unable to initiate inflammatory responses by themselves, yet are implicated in the pathogenesis of various inflammatory disorders. However, the mechanism for such an apparent discrepancy is still unclear. We utilized SR-A−/−, MARCO−/−, and SR-A−/−-MARCO−/− mice, along with microbe-derived, environmental, and synthetic polyanions to assess the inflammatory responses following combinatorial ligation of SR-A/MARCO and selected Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)–like receptors (NLRs) by their shared ligands. In addition to ligating SR-A and MARCO, these agonists also selectively activated the cell-surface sensor TLR4, endosomal TLR3, and the cytosolic NOD2 and NALP3 (NACHT domain–, leucine-rich repeat–, and pyrin domain–containing protein 3). We show that, following recognition of common ligands, SR-A and MARCO attenuate TLR4-mediated responses while enhancing responses by the intracellular TLR3, NOD2, and NALP3. We conclude that SR-A/MARCO-mediated rapid ligand internalization prevented sensing by surface TLRs while increasing ligand availability in intracellular compartments, thus allowing sensing and robust responses by intracellular sensors.
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Shehab, Marwa, Rana Jammaz, Noor Salloum, and Elias A. Rahal. "Endosomal Toll-Like Receptors (TLRs) mediate enhancement of IL-17A production triggered by Epstein-Barr virus (EBV) DNA in mice." Journal of Infection in Developing Countries 12, no. 02.1 (February 22, 2018): 26S. http://dx.doi.org/10.3855/jidc.10074.
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Introduction: EBV has long-been associated with autoimmune disorders. We have previously demonstrated that EBV DNA increases the production of IL-17A in mice. This property may play a role in the association of EBV with autoimmune diseases. The objective of this study was to elucidate mechanisms through which EBV DNA modulates IL-17A levels in mice.
Methodology: To study the potential role of endosomal receptors in detecting EBV DNA, chloroquine, an endosomal maturation inhibitor, was used to treat mouse peripheral blood mononuclear cells (PBMCs) in the presence or absence of EBV DNA. IL-17A levels were then assessed by ELISA. Subsequently, to determine whether TLR3, 7 or 9 played a role in this pathway, specific inhibitors were used for these TLRs both in mouse PBMCs and in vivo in BALB/c mice treated with the viral DNA; IL-17A levels were then similarly assessed.
Results: IL-17A production was enhanced from mouse PBMCs cultured with EBV DNA; pre-incubation of PBMCs with chloroquine significantly reduced its production. When cells were cultured with EBV DNA and a TLR3, 7 or 9 inhibitor, a significant decrease in IL-17A levels was detected. A similar decrease in the EBV DNA-triggered IL-17A production in mice was observed when animals were treated with the TLR inhibitors.
Conclusion: Endosomal TLRs appear to be involved in recognizing EBV DNA and subsequently triggering IL-17A production in mice. Targeting these receptors in EBV positive subjects with autoimmunity may be useful pending investigations assessing whether they play a similar role in humans.
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Lentini, Germana, Agata Famà, Giuseppe Valerio De Gaetano, Roberta Galbo, Francesco Coppolino, Mario Venza, Giuseppe Teti, and Concetta Beninati. "Role of Endosomal TLRs in Staphylococcus aureus Infection." Journal of Immunology 207, no. 5 (August 6, 2021): 1448–55. http://dx.doi.org/10.4049/jimmunol.2100389.
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Dela Justina, Vanessa, Fernanda R. Giachini, Fernanda Priviero, and R. Clinton Webb. "Double-stranded RNA and Toll-like receptor activation: a novel mechanism for blood pressure regulation." Clinical Science 134, no. 2 (January 2020): 303–13. http://dx.doi.org/10.1042/cs20190913.
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Abstract Toll-like receptors (TLRs), such as TLR4 and 9, recognize pathogen-associated molecular pattern (PAMPs) and danger-associated molecular patterns (DAMPs) and are associated with increased blood pressure (BP). TLR3, residing in the endosomal compartment, is activated by viral double-stranded RNA (dsRNA) leading to activation of TIR receptor domain-containing adaptor inducing IFN-β (TRIF) dependent pathway. Besides foreign pathogens, the immune system responds to endogenous markers of cellular damage such as mitochondrial dsRNA (mtdsRNA). New evidence has shown a link between dsRNA and increased BP. Moreover, TLR3 activation during pregnancy was demonstrated to develop preeclampsia-like symptoms in both rats and mice. Hence, we hypothesize that the dsRNA derived from viral nucleic acids or cellular damage (mtdsRNA) will increase the inflammatory state through activation of TLR3, contributing to vascular dysfunction and increased BP. Therefore, inhibition of TLR3 could be a therapeutic target for the treatment of hypertension with potential improvement in vascular reactivity and consequently, a decrease in BP.
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Lehnardt, Seija, Thomas Wallach, Vitka Gres, and Philipp Henneke. "Guardians of neuroimmunity – Toll-like receptors and their RNA ligands." Neuroforum 25, no. 3 (August 7, 2019): 185–93. http://dx.doi.org/10.1515/nf-2018-0032.
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Abstract RNA-sensing Toll-like receptors (TLRs) are mostly associated with the recognition of viruses. However, over the last years it has become clear that the function and relevance of these receptors are far more complex. They are essential for the recognition of bacteria, fungi and parasites, leading to transcriptional activation of central nervous system (CNS) resident and invading myeloid cells during infectious meningitis and encephalitis. Moreover, host-derived RNA species interact with TLRs. Injured CNS neurons release small RNAs, e. g. microRNAs, into the extracellular space. Neighboring neurons and microglia take up these RNA molecules via the endosomal route, which provides the opportunity for activation of endosomal TLRs. This process contributes to neuroinflammation and further neuronal injury, thus closing the vicious cycle of CNS damage, as it may occur in numerous CNS disorders including neurodegenerative diseases.
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Mielcarska, Matylda Barbara, Justyna Struzik, and Felix Ngosa Toka. "Tlr3 interacts with ESCRT-I components Tsg101 and Hcrp1 in mouse astrocyte cell line." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 15.02. http://dx.doi.org/10.4049/jimmunol.206.supp.15.02.
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Abstract It is established now that ESCRT (endosomal sorting complex required for transport) complexes participate in the trafficking of endosomal Toll-like receptors (TLRs), which are relevant in the regulation of the TLR-mediated immune response. TLR3 plays a vital role in the innate immune control of herpes simplex type 1 virus (HSV-1) infection in the brain, however, the process of TLR3 delivery to the ligand recognition site and fate as endosomal cargo including the receptor degradation await explication. Proximity ligation assays in TLR3 agonist, poly(I:C) stimulated or unstimulated murine astrocytes, confirmed the association of Tlr3 with Tsg101 and Hcrp1, ESCRT-I subunits essential for the lysosomal sorting of ubiquitinated membrane receptors. The interaction of Tlr3 and ESCRT-I components was prominent in the first hour and 24 h after poly(I:C) addition. TLR3 was highly ubiquitinated in cells at all studied times, while the interaction of Hrs, a core component of ESCRT-0 and ESCRT-I, and Tlr3, as well as Hrs and Tsg101, and Hrs and Hcrp1, increased in the first hour of stimulation, but 24 h following stimulation returned to levels observed in unstimulated cells. Results suggest a possible role of ESCRT-I in prolongation of TLR3 signaling and/or receptor degradation, prompting investigation whether Tsg101 and Hcrp1 influence Tlr3 transportation in cells of the central nervous system, which would portray ESCRT-I as a possible modulation target regarding TLR3-mediated antiviral response in the brain.
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Lu, Chih-Hao, Chao-Yang Lai, Da-Wei Yeh, Yi-Ling Liu, Yu-Wen Su, Li-Chung Hsu, Chung-Hsing Chang, S. L. Catherine Jin, and Tsung-Hsien Chuang. "Involvement of M1 Macrophage Polarization in Endosomal Toll-Like Receptors Activated Psoriatic Inflammation." Mediators of Inflammation 2018 (December 16, 2018): 1–14. http://dx.doi.org/10.1155/2018/3523642.
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Psoriasis is a chronic inflammatory skin disorder that affects ~2%–3% of the worldwide population. Inappropriate and excessive activation of endosomal Toll-like receptors 7, 8, and 9 (TLRs 7–9) at the psoriatic site has been shown to play a pathogenic role in the onset of psoriasis. Macrophage is a major inflammatory cell type that can be differentiated into phenotypes M1 and M2. M1 macrophages produce proinflammatory cytokines, and M2 macrophages produce anti-inflammatory cytokines. The balance between these two types of macrophages determines the progression of various inflammatory diseases; however, whether macrophage polarization plays a role in psoriatic inflammation activated by endosomal TLRs has not been investigated. In this study, we investigated the function and mechanism of macrophages related to the pathogenic role of TLRs 7–9 in the progression of psoriasis. Analysis of clinical data in database revealed significantly increased expression of macrophage markers and inflammatory cytokines in psoriatic tissues over those in normal tissues. In animal studies, depletion of macrophages in mice ameliorated imiquimod, a TLR 7 agonist-induced psoriatic response. Imiquimod induced expression of genes and cytokines that are signature of M1 macrophage in the psoriatic lesions. In addition, treatment with this TLR 7 agonist shifted macrophages in the psoriatic lesions to a higher M1/M2 ratio. Both of the exogenous and endogenous TLR 7–9 ligands activated M1 macrophage polarization. M1 macrophages expressed higher levels of proinflammatory cytokines and TLRs 7–9 than M2 macrophages. These results suggest that by rendering macrophages into a more inflammatory status and capable of response to their ligands in the psoriatic sites, TLR 7–9 activation drives them to participate in endosomal TLR-activated psoriatic inflammation, resulting in an amplified inflammatory response. Our results also suggest that blocking M1 macrophage polarization could be a strategy which enables inhibition of psoriatic inflammation activated by these TLRs.
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Dominguez, Donye, Natalia Chernyak, Monica guan, Yushang Chou, Alan Long, Lei Qin, Lisa Cole, et al. "Robust antitumor effects of SNA-based T cell therapy." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 134.7. http://dx.doi.org/10.4049/jimmunol.202.supp.134.7.
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Abstract The use of toll like receptor (TLR) agonists for immunotherapy remains under intense investigation. Activation of TLRs unleash the power of dendritic cells (DCs) to induce a robust antitumor CD8+ T cell response. However, the role of TLRs in CD8+ T cells has been largely overlooked. T cells do express endosomal TLR9, but it is not readily targetable in these non-phagocytic cells. Using the novel delivery platform of spherical nucleic acids (SNAs), we have devised a way to efficiently activate endosomal TLR9 by CpG, while simultaneously delivering tumor antigens to intracellular compartments in T cells. Activation of TLR9 in CD8+ T cells endows them with special properties. First, T cells themselves express appreciable levels of co-stimulatory molecules after activation of CpG derived from SNAs, thereby functioning as antigen presenting cells to cross-prime antigen-specific CD8+ T cells. Second, SNA activated T cells act as chaperones (T chaperones) of SNA material. Through exosomal transfer, T chaperones shuttle CpG and antigen, mouse or human, to bystander DCs for further cross-presentation of antigen. Third, antigen specific T chaperones are highly cytotoxic and resist tumor induced immune suppression. These combined effects of adoptive therapy using tumor antigen specific T chaperones achieve tumor regression in aggressive melanoma models without irradiation or cytokine supplementation, which complicate T cell-based therapies. T chaperones represent a novel cell-based therapy that co-delivers adjuvant and antigen to efficiently boost antitumor CD8+ T cell activity, eliminating the need for viral manipulation and shortens the long, and costly, production time associated with other T cell therapies.
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Jiang, Lihua, Liyi Pei, Ping Wang, Liqin Liu, Gong Li, Binjian Liu, Zhenming Lǚ, Tabata Hiromasa, Hao Pan, and Atsushi Ogura. "Molecular Characterization and Evolution Analysis of Two Forms of TLR5 and TLR13 Genes Base on Larimichthys crocea Genome Data." International Journal of Genomics 2020 (December 9, 2020): 1–17. http://dx.doi.org/10.1155/2020/4895037.
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TLRs (Toll-like receptors) are essential in host defense against pathogens. There are two types of TLR5, namely, membrane form of TLR5 (TLR5M) and soluble form of TLR5 (TLR5S), both of which perform a crucial role in flagellin response. TLR13 is a TLR that localizes to endosomes and recognizes nucleic acids released by internal microorganisms, including viruses, bacteria, and fungi. Here, the full-length coding sequence (CDS), protein structure, and immune response and subcellular localization of TLR5 (TLR5S) and TLR13 were characterized in large yellow croaker (Larimichthys crocea). These TLRs share high sequence homology with other ichthyic TLRs, while also having their own characters; qtPCR was determined and the results found that the three genes were constitutively expressed in all examined tissues: TLR5M was highly expressed in the spleen and liver; TLR13 expression was high in the kidney, liver, and spleen. And TLRs were upregulated following stimulation with Vibrio parahaemolyticus in the liver, spleen, and kidney. Immunofluorescence staining revealed that TLR5M were localized in the cytoplasm, while TLR5S and TLR13 were in the endosome. The evolutionary analysis has shown that TLR13 was clustered with TLR11, 19, 20, 21, and 22, while TLR5 and TLR3 were classified into a group; these results suggest that TLRs are vital in the defense of L. crocea against bacterial infection and further increase our understanding of TLR function in innate immunity in teleosts.
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Khan, Burhan, Piyali Mukherjee, Katherine Taylor, Tyson Woods, Clayton Winkler, and Karin Peterson. "The role of SARM1 in Toll-like receptor and viral-induced neuronal apoptosis (INM7P.347)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 194.4. http://dx.doi.org/10.4049/jimmunol.194.supp.194.4.
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Abstract Neuronal apoptosis is a key aspect of several neurological diseases but the mechanisms leading to apoptosis are not well understood. Recent studies have suggested that activation of Pattern Recognition Receptors (PRRs) of neurons leads to neuronal apoptosis, even in the absence of pathogen insult. For example, combined stimulation of neurons through toll-like receptors (TLRs) TLR7 and TLR9 results in significant apoptosis. Using neurons from transgenic mice, we found that TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required sterile alpha armadillo motif (SARM1), which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation and TLR-induced apoptosis. These studies indicate a previously unknown pathway for TLR-mediated neuronal apoptosis and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage. SARM1 also induces neuronal apoptosis in a Bunyavirus infection model through another PRR pathway, suggesting that SARM1 may be a common mechanism for innate-immune driven neuronal apoptosis. Our current studies are focused on understanding the interaction of SARM1 with other cellular proteins to identify: 1) the mechanism that regulates SARM1 localization to mitochondria, and 2) the mechanism by which SARM1 influences mitochondrial trafficking.
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Casiraghi, Costanza, Tatiana Gianni, and Gabriella Campadelli-Fiume. "αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors." Journal of Virology 90, no. 8 (February 3, 2016): 4243–48. http://dx.doi.org/10.1128/jvi.03175-15.
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We report that αvβ3 integrin strongly affects the innate immune response in epithelial cells. αvβ3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by αvβ3 integrin. The boosting was exerted specifically by αvβ3 integrin but not by αvβ6 or αvβ8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response.
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Horton, Christopher G., Zi-jian Pan, and A. Darise Farris. "Targeting Toll-Like Receptors for Treatment of SLE." Mediators of Inflammation 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/498980.
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Toll-like receptors (TLRs) are important innate immune receptors for the identification and clearance of invading pathogens. Twelve TLRs that recognize various conserved components of microorganisms are currently known. Among these, the endosomal TLRs 3, 7/8, and 9 recognize dsRNA, ssRNA, and CpG DNA, respectively. Nucleic acid-sensing TLRs, TLR 7 in particular, have been implicated in systemic lupus erythematosus (SLE) and are thought to exacerbate disease pathology. Activation of these TLRs results in the production of inflammatory cytokines and type I interferon. Genome-wide association studies, single nucleotide polymorphism analyses as well as experimental mouse models have provided evidence of TLR signaling involvement in SLE and other autoimmune diseases. Since activation of these receptor pathways promotes autoimmune phenotypes, inhibitory drugs that target these pathways constitute important new therapeutic strategies for the treatment of systemic autoimmunity.
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Andón, Fernando Torres, Sergio Leon, Aldo Ummarino, Esther Redin, Paola Allavena, Diego Serrano, Clement Anfray, and Alfonso Calvo. "Innate and Adaptive Responses of Intratumoral Immunotherapy with Endosomal Toll-Like Receptor Agonists." Biomedicines 10, no. 7 (July 4, 2022): 1590. http://dx.doi.org/10.3390/biomedicines10071590.
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Toll-like receptors (TLRs) are natural initial triggers of innate and adaptive immune responses. With the advent of cancer immunotherapy, nucleic acids engineered as ligands of endosomal TLRs have been investigated for the treatment of solid tumors. Despite promising results, their systemic administration, similarly to other immunotherapies, raises safety issues. To overcome these problems, recent studies have applied the direct injection of endosomal TLR agonists in the tumor and/or draining lymph nodes, achieving high local drug exposure and strong antitumor response. Importantly, intratumoral delivery of TLR agonists showed powerful effects not only against the injected tumors but also often against uninjected lesions (abscopal effects), resulting in some cases in cure and antitumoral immunological memory. Herein, we describe the structure and function of TLRs and their role in the tumor microenvironment. Then, we provide our vision on the potential of intratumor versus systemic delivery or vaccination approaches using TLR agonists, also considering the use of nanoparticles to improve their targeting properties. Finally, we collect the preclinical and clinical studies applying intratumoral injection of TLR agonists as monotherapies or in combination with: (a) other TLR or STING agonists; (b) other immunotherapies; (c) radiotherapy or chemotherapy; (d) targeted therapies.
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McDaniel, Margaret, Charles Tracy, Helmut Kramer, and Chandrashekhar Pasare. "Role of Vps33B in regulation of inflammatory responses." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 46.10. http://dx.doi.org/10.4049/jimmunol.200.supp.46.10.
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Abstract Macrophages and dendritic cells use pattern recognition receptors (PRRs) to sense their surroundings and respond to pathogenic stimuli. Engagement of PRRs, such as Toll-like receptors (TLRs), results in accelerated phagocytosis of cargo, activation of anti-microbial responses, and induction of phagosomal and endosomal maturation. Endo/phagosomal maturation and endo/phagolysosome fusion likely plays a critical role in regulation of TLR signaling and outcome of inflammatory responses following microbial recognition. Previous work in the lab has shown that Vps (Vacuolar protein sorting) 33B specifically regulates endosomal maturation following TLR activation, thus influencing the outcome of downstream signaling. In the absence of Vps33B, drosophila hemocytes and mouse macrophages elicit an enormous inflammatory response to live or dead bacterial challenge, yet are unable to degrade the bacterial cargo. This exaggerated immune response is a direct result of accumulated TLRs and ligands that continue to signal while stuck in late endosomal compartments. We have now discovered that this inability to degrade pathogenic cargo has critical implications for adaptive immunity. Absence of Vps33B leads to enhanced maturation of DCs, yet these DCs are unable to effectively prime CD4 T cells, presumably due to lack of processing endocytosed cargo. Mice that specifically lack Vps33B in DCs were unable to activate antigen-specific CD4 T cells in vivo, leading to defective Th1 and Th17 priming. Collectively, our results suggest an important role for Vps33B in both innate and adaptive immune responses. Further work will elucidate the molecular mechanisms of regulation of Vps33B downstream of TLRs and its impact on host immunity.
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Dondalska, Aleksandra, Sandra Axberg Pålsson, and Anna-Lena Spetz. "Is There a Role for Immunoregulatory and Antiviral Oligonucleotides Acting in the Extracellular Space? A Review and Hypothesis." International Journal of Molecular Sciences 23, no. 23 (November 23, 2022): 14593. http://dx.doi.org/10.3390/ijms232314593.
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Here, we link approved and emerging nucleic acid-based therapies with the expanding universe of small non-coding RNAs (sncRNAs) and the innate immune responses that sense oligonucleotides taken up into endosomes. The Toll-like receptors (TLRs) 3, 7, 8, and 9 are located in endosomes and can detect nucleic acids taken up through endocytic routes. These receptors are key triggers in the defense against viruses and/or bacterial infections, yet they also constitute an Achilles heel towards the discrimination between self- and pathogenic nucleic acids. The compartmentalization of nucleic acids and the activity of nucleases are key components in avoiding autoimmune reactions against nucleic acids, but we still lack knowledge on the plethora of nucleic acids that might be released into the extracellular space upon infections, inflammation, and other stress responses involving increased cell death. We review recent findings that a set of single-stranded oligonucleotides (length of 25–40 nucleotides (nt)) can temporarily block ligands destined for endosomes expressing TLRs in human monocyte-derived dendritic cells. We discuss knowledge gaps and highlight the existence of a pool of RNA with an approximate length of 30–40 nt that may still have unappreciated regulatory functions in physiology and in the defense against viruses as gatekeepers of endosomal uptake through certain routes.
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Hatton, Alexis Alexandria, Kelly Shepardson, Yang Wang, Laura Logan Johns, Cheri Goodall, Trevor Douglas, and Agnieszka Rynda-Apple. "Unique MyD88/TRAM signaling post TLR2/6 recognition of conserved viral architectures results in anti-viral immunity and improved clearance of secondary bacterial infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 70.9. http://dx.doi.org/10.4049/jimmunol.204.supp.70.9.
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Abstract Respiratory virus infections can either reduce or increase host susceptibility to subsequent secondary bacterial infections (SBI). Recently, we discovered that the anti-viral immune response initiated by the recognition of exogenous pattern of virus architectures, namely the repeating protein subunit pattern (RPSP), results in improved clearance of S. aureus during SBI in mice. The RPSP is likely conserved in all viruses, suggesting a generalized mode of viral pattern recognition not specific to any single virus. Thus, we identified RPSP as a new PAMP and found it to be recognized by the TLR2/6 heterodimer on the surface of macrophages. We found that this RPSP recognition occurs prior to particle internalization and independent of virus infection. TLRs are known to signal from either the cell surface, through MyD88/Mal, or from the endosome, through TRAM/TRIF, for the induction of inflammatory responses or type I IFNs, respectively. We found that when compared to WT macrophages, tram−/− macrophages exhibited diminished RPSP internalization by confocal microscopy and flow cytometry. However, blocking endosomal acidification by Bafilomycin A1 did not reduce S. aureus killing by RPSP-treated macrophages. This suggests that a non-canonical endosomal signaling pathway may be induced upon RPSP exposure. Indeed, using knockout mice we found that type I IFN, but also MyD88 signaling are critical for improved S. aureus clearance post RPSP. Our results indicate that the recognition of RPSP by TLR2/6 activates a unique intracellular signaling pathway, specifically a combination of the two known pathways, that results in type I IFN-dependent improvement in S. aureus killing by macrophages.