The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
-
unc93b1 restricts systemic lethal inflammation by orchestrating toll like Receptor 7 and 9 trafficking
Immunity, 2011Co-Authors: Ryutaro Fukui, Shizuo Akira, Atsuo Kanno, Masahiro Onji, Shinichiroh Saitoh, Takuma Shibata, Morikazu Onji, Mitsuru Matsumoto, Nobuaki Yoshida, Kensuke MiyakeAbstract:Summary Toll-Like Receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4 + T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.
-
antigen specific t cell responses to a recombinant fowlpox virus are dependent on myd88 and interleukin 18 and independent of toll like Receptor 7 tlr7 and tlr9 mediated innate immune recognition
Journal of Virology, 2011Co-Authors: Erin L Lousberg, Weisan Chen, Shizuo Akira, Satoshi Uematsu, Kerrilyn R Diener, Cara K Fraser, Simon Phipps, Paul S Foster, Sarah A Robertson, Michael P BrownAbstract:Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPVOVA), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-Like Receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPVOVA in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 Receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.
-
antiviral protein viperin promotes toll like Receptor 7 and toll like Receptor 9 mediated type i interferon production in plasmacytoid dendritic cells
Immunity, 2011Co-Authors: Tatsuya Saitoh, Osamu Takeuchi, Takashi Satoh, Naoki Yamamoto, Satoshi Uematsu, Taro Kawai, Shizuo AkiraAbstract:Toll-Like Receptor 7 (TLR7) and TLR9 sense viral nucleic acids and induce production of type I interferon (IFN) by plasmacytoid dendritic cells (pDCs) to protect the host from virus infection. We showed that the IFN-inducible antiviral protein Viperin promoted TLR7- and TLR9-mediated production of type I IFN by pDCs. Viperin expression was potently induced after TLR7 or TLR9 stimulation and Viperin localized to the cytoplasmic lipid-enriched compartments, lipid bodies, in pDCs. Viperin interacted with the signal mediators IRAK1 and TRAF6 to recruit them to the lipid bodies and facilitated K63-linked ubiquitination of IRAK1 to induce the nuclear translocation of transcription factor IRF7. Loss of Viperin reduced TLR7- and TLR9-mediated production of type I IFN by pDCs. However, Viperin was dispensable for the production of type I IFN induced by intracellular nucleic acids. Thus, Viperin mediates its antiviral function via the regulation of the TLR7 and TLR9-IRAK1 signaling axis in pDCs.
-
bacterial recognition by tlr7 in the lysosomes of conventional dendritic cells
Nature Immunology, 2009Co-Authors: Giuseppe Mancuso, Shizuo Akira, Maria Elsa Gambuzza, Angelina Midiri, Carmelo Biondo, Salvatore Papasergi, Giuseppe Teti, Concetta BeninatiAbstract:Little is known of how and where bacterial recognition triggers the induction of type I interferon. Whether the type of recognition Receptor used in these responses is determined by the subcellular location of bacteria is not understood. Here we show that phagosomal bacteria such as group B streptococcus, but not cytosolic bacteria, potently induced interferon in conventional dendritic cells by a mechanism that required Toll-Like Receptor 7, the adaptor MyD88 and the transcription factor IRF1, all of which localized together with bacterial products in degradative vacuoles bearing lysosomal markers. Thus, this cell type-specific recognition pathway links lysosomal recognition of bacterial RNA with a robust, host-protective interferon response.
-
requirement of toll like Receptor 7 for pristane induced production of autoantibodies and development of murine lupus nephritis
Arthritis & Rheumatism, 2008Co-Authors: Emina Savarese, Shizuo Akira, Rahul D Pawar, Hansjoachim Anders, Christian Steinberg, Wolfgang Reindl, Anne KrugAbstract:Objective The detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-Like Receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model. Methods Serum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7–deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry. Results We found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas anti–double-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7–deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis. Conclusion TLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.
Richard A Flavell - One of the best experts on this subject based on the ideXlab platform.
-
toll like Receptor 7 mitigates lethal west nile encephalitis via interleukin 23 dependent immune cell infiltration and homing
Immunity, 2009Co-Authors: Amber T Kaplan, Terrence Town, Ruth R Montgomery, John F Anderson, Feng Qian, Tian Wang, Richard A FlavellAbstract:Summary West Nile virus (WNV), a mosquito-transmitted single-stranded RNA (ssRNA) flavivirus, causes human disease of variable severity. We investigated Toll-Like Receptor 7-deficient ( Tlr7 −/− ) and myeloid differentiation factor 88-deficient ( Myd88 −/− ) mice, which both have defective recognition of ssRNA, and found increased viremia and susceptibility to lethal WNV infection. Despite increased tissue concentrations of most innate cytokines, CD45 + leukocytes and CD11b + macrophages failed to home to WNV-infected cells and infiltrate into target organs of Tlr7 −/− mice. Tlr7 −/− mice and macrophages had reduced interleukin-12 (IL-12) and IL-23 responses after WNV infection, and mice deficient in IL-12 p40 and IL-23 p40 ( Il12b −/− ) or IL-23 p19 ( Il23a −/− ), but not IL-12 p35 ( Il12a −/− ), responded similarly to Tlr7 −/− mice, with increased susceptibility to lethal WNV encephalitis. Collectively, these results demonstrate that TLR7 and IL-23-dependent WNV responses represent a vital host defense mechanism that operates by affecting immune cell homing to infected target cells.
-
control of toll like Receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation
Immunity, 2007Co-Authors: Jonathan A Deane, Terrence Town, Richard A Flavell, Prapaporn Pisitkun, Rebecca S Barrett, Lionel Feigenbaum, Jerrold M Ward, Silvia BollandAbstract:Summary Nucleic acid-binding innate immune Receptors such as Toll-Like Receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa , which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
-
toll like Receptor 7 and tlr9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus
Immunity, 2006Co-Authors: Sean R Christensen, Richard A Flavell, Jonathan Shupe, Kevin M Nickerson, Michael Kashgarian, Mark J ShlomchikAbstract:Antibodies (Abs) to RNA- and DNA-containing autoantigens are characteristic of systemic lupus erythematosus (SLE). We showed previously that Toll-Like Receptor (TLR) 9, recognizing DNA, is required for the spontaneous generation of DNA autoantibodies, but not for the development of lupus nephritis in susceptible mice. We report that lupus-prone mice deficient in TLR7, a Receptor for ssRNA, failed to generate Abs to RNA-containing antigens (Ags) such as Smith (Sm) Ag. TLR9 and TLR7 also had dramatic effects on clinical disease in lupus-prone mice. In the absence of TLR9, autoimmune disease was exacerbated, lymphocytes and plasmacytoid DCs were more activated, and serum IgG and IFN-α were increased. In contrast, TLR7-deficient mice had ameliorated disease, decreased lymphocyte activation, and decreased serum IgG. These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways. These results have important implications for TLR-directed therapy of autoimmune disease.
-
rna associated autoantigens activate b cells by combined b cell antigen Receptor toll like Receptor 7 engagement
Journal of Experimental Medicine, 2005Co-Authors: Courtney Broughton, Richard A Flavell, Shizuo Akira, Abigail S Tabor, Mark J Mamula, Sean R Christensen, Mark J Shlomchik, Gregory A Viglianti, Ian R Rifkin, Ann MarshakrothsteinAbstract:Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837–847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen Receptor (BCR) and Toll-Like Receptor (TLR) 9. We demonstrate that this two-Receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN- α , a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers.
-
Recognition of single-stranded RNA viruses by Toll-Like Receptor 7
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Jennifer M. Lund, Lena Alexopoulou, Ayuko Sato, Margaret Karow, Niels C. Adams, Nicholas W. Gale, Akiko Iwasaki, Richard A FlavellAbstract:Viral infection of mammalian host results in the activation of innate immune responses. Toll-Like Receptors (TLRs) have been shown to mediate the recognition of many types of pathogens, including viruses. The genomes of viruses possess unique characteristics that are not found in mammalian genomes, such as high CpG content and double-stranded RNA. These genomic nucleic acids serve as molecular signatures associated with viral infections. Here we show that TLR7 recognizes the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus. The recognition of these viruses by plasmacytoid dendritic cells and B cells through TLR7 results in their activation of costimulatory molecules and production of cytokines. Moreover, this recognition required intact endocytic pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88 demonstrated reduced responses to in vivo infection with vesicular stomatitis virus. These results demonstrate microbial ligand recognition by TLR7 and provide insights into the pathways used by the innate immune cells in the recognition of viral pathogens.
Susumu Uchiyama - One of the best experts on this subject based on the ideXlab platform.
-
structural analysis reveals that toll like Receptor 7 is a dual Receptor for guanosine and single stranded rna
Immunity, 2016Co-Authors: Z Zhang, Umeharu Ohto, Takuma Shibata, Hiromi Tanji, Masato Taoka, Yoshio Yamauchi, Toshiaki Isobe, Elena Krayukhina, Susumu UchiyamaAbstract:Toll-Like Receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands. The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual Receptor for guanosine and uridine-containing ssRNA. Our findings have important implications for understanding of TLR7 function, as well as for therapeutic manipulation of TLR7 activation.
Caetano Reis E Sousa - One of the best experts on this subject based on the ideXlab platform.
-
processing of human toll like Receptor 7 by furin like proprotein convertases is required for its accumulation and activity in endosomes
Immunity, 2013Co-Authors: Madeleine Maria Hipp, Caetano Reis E Sousa, Dawn Shepherd, Uzi Gileadi, Michael C Aichinger, Benedikt M Kessler, Mariola J Edelmann, Rachid Essalmani, Nabil G Seidah, Vincenzo CerundoloAbstract:Toll-Like Receptor 7 (TLR7) triggers antiviral immune responses by recognizing viral single-stranded RNA in endosomes, but the biosynthetic pathway of human TLR7 (hTLR7) remains unclear. Here, we show that hTLR7 is proteolytically processed and that the C-terminal fragment selectively accumulates in endocytic compartments. hTLR7 processing occurred at neutral pH and was dependent on furin-like proprotein convertases (PCs). Furthermore, TLR7 processing was required for its functional response to TLR7 agonists such as R837 or influenza virus. Notably, proinflammatory and differentiation stimuli increased the expression of furin-like PCs in immune cells, suggesting a positive feedback mechanism for TLR7 processing during infection. Because self-RNA can under certain conditions activate TLR7 and trigger autoimmunity, our results identify furin-like PCs as a possible target to attenuate TLR7-dependent autoimmunity and other immune pathologies.
-
nucleic acid agonists for toll like Receptor 7 are defined by the presence of uridine ribonucleotides
European Journal of Immunology, 2006Co-Authors: Shizuo Akira, Sandra S. Diebold, Catherine Massacrier, Carine Paturel, Yannis Morel, Caetano Reis E SousaAbstract:Toll-Like Receptor 7 (TLR7) mediates innate responses by responding to viral RNA in endocytic compartments. However, the molecular pattern recognised by TLR7 and whether it differs between RNA of viral and self origin remains unclear. Here, we identify nucleic acids that act as TLR7 agonists for mouse and human cells. We show that uridine and ribose, the two defining features of RNA, are both necessary and sufficient for TLR7 stimulation, and that short single-stranded RNA (ssRNA) act as TLR7 agonists in a sequence-independent manner as long as they contain several uridines in close proximity. Consistent with the notion that TLR7 lacks specificity for sequence motifs, we show that it is triggered equally efficiently by viral or self RNA delivered to endosomes. Our results support the notion that TLR7 recognises uracil repeats in RNA and that it discriminates between viral and self ligands on the basis of endosomal accessibility rather than sequence.
-
innate antiviral responses by means of tlr7 mediated recognition of single stranded rna
Science, 2004Co-Authors: Sandra S. Diebold, Tsuneyasu Kaisho, Hiroaki Hemmi, Shizuo Akira, Caetano Reis E SousaAbstract:Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-α in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-Like Receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
Terrence Town - One of the best experts on this subject based on the ideXlab platform.
-
toll like Receptor 7 mitigates lethal west nile encephalitis via interleukin 23 dependent immune cell infiltration and homing
Immunity, 2009Co-Authors: Amber T Kaplan, Terrence Town, Ruth R Montgomery, John F Anderson, Feng Qian, Tian Wang, Richard A FlavellAbstract:Summary West Nile virus (WNV), a mosquito-transmitted single-stranded RNA (ssRNA) flavivirus, causes human disease of variable severity. We investigated Toll-Like Receptor 7-deficient ( Tlr7 −/− ) and myeloid differentiation factor 88-deficient ( Myd88 −/− ) mice, which both have defective recognition of ssRNA, and found increased viremia and susceptibility to lethal WNV infection. Despite increased tissue concentrations of most innate cytokines, CD45 + leukocytes and CD11b + macrophages failed to home to WNV-infected cells and infiltrate into target organs of Tlr7 −/− mice. Tlr7 −/− mice and macrophages had reduced interleukin-12 (IL-12) and IL-23 responses after WNV infection, and mice deficient in IL-12 p40 and IL-23 p40 ( Il12b −/− ) or IL-23 p19 ( Il23a −/− ), but not IL-12 p35 ( Il12a −/− ), responded similarly to Tlr7 −/− mice, with increased susceptibility to lethal WNV encephalitis. Collectively, these results demonstrate that TLR7 and IL-23-dependent WNV responses represent a vital host defense mechanism that operates by affecting immune cell homing to infected target cells.
-
control of toll like Receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation
Immunity, 2007Co-Authors: Jonathan A Deane, Terrence Town, Richard A Flavell, Prapaporn Pisitkun, Rebecca S Barrett, Lionel Feigenbaum, Jerrold M Ward, Silvia BollandAbstract:Summary Nucleic acid-binding innate immune Receptors such as Toll-Like Receptor 7 (TLR7) and TLR9 have been implicated in the development of some autoimmune pathologies. The Y chromosome-linked genomic modifier Yaa , which correlates with a duplication of Tlr7 and 16 other genes, exacerbates lupus-like syndromes in several mouse strains. Here we demonstrated that duplication of the Tlr7 gene was the sole requirement for this accelerated autoimmunity, because reduction of Tlr7 gene dosage abolished the Yaa phenotype. Further, we described new transgenic lines that overexpressed TLR7 alone and found that spontaneous autoimmunity developed beyond a 2-fold increase in TLR7 expression. Whereas a modest increase in Tlr7 gene dosage promoted autoreactive lymphocytes with RNA specificities and myeloid cell proliferation, a substantial increase in TLR7 expression caused fatal acute inflammatory pathology and profound dendritic cell dysregulation. These results underscore the importance of tightly regulating expression of TLR7 to prevent spontaneous triggering of harmful autoreactive and inflammatory responses.
