DOCSLIB.ORG

Not Signaling Mechanisms of Innate Immune Sensing but Human Tlrs 10 and 1 Share Common

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Not Signaling Mechanisms of Innate Immune Sensing but Human Tlrs 10 and 1 Share Common Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling This information is current as Yue Guan, Diana Rose E. Ranoa, Song Jiang, Sarita K. of September 28, 2021. Mutha, Xinyan Li, Jerome Baudry and Richard I. Tapping J Immunol 2010; 184:5094-5103; Prepublished online 26 March 2010; doi: 10.4049/jimmunol.0901888 http://www.jimmunol.org/content/184/9/5094 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/03/25/jimmunol.090188 Material 8.DC1 http://www.jimmunol.org/ References This article cites 74 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/184/9/5094.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling Yue Guan,* Diana Rose E. Ranoa,* Song Jiang,* Sarita K. Mutha,† Xinyan Li,* Jerome Baudry,‡ and Richard I. Tapping*,x TLRs are central receptors of the innate immune system that drive host inflammation and adaptive immune responses in response to invading microbes. Among human TLRs, TLR10 is the only family member without a defined agonist or function. Phylogenetic analysis reveals that TLR10 is most related to TLR1 and TLR6, both of which mediate immune responses to a variety of microbial and fungal components in cooperation with TLR2. The generation and analysis of chimeric receptors containing the extracellular recognition domain of TLR10 and the intracellular signaling domain of TLR1, revealed that TLR10 senses triacylated lipopep- tides and a wide variety of other microbial-derived agonists shared by TLR1, but not TLR6. TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion. Downloaded from Computational modeling and mutational analysis of TLR10 showed preservation of the essential TLR2 dimer interface and lipopeptide-binding channel found in TLR1. Coimmunoprecipitation experiments indicate that, similar to TLR2/1, TLR2/10 complexes recruit the proximal adaptor MyD88 to the activated receptor complex. However, TLR10, alone or in cooperation with TLR2, fails to activate typical TLR-induced signaling, including NF-kB–, IL-8–, or IFN-b–driven reporters. We conclude that human TLR10 cooperates with TLR2 in the sensing of microbes and fungi but possesses a signaling function distinct from that of other TLR2 subfamily members. The Journal of Immunology, 2010, 184: 5094–5103. http://www.jimmunol.org/ he innate immune system is the first line of defense in fense, monocytes/macrophages express most TLRs (6), whereas response to an invading pathogen. Cellular innate immune the expression of individual TLRs in dendritic cells depends upon T defenses are necessary for the direct killing of pathogens, their subtype (9, 10). The microbial agonists for TLRs include and they also mediate the immediate release of proinflammatory a wide variety of structures. For example, TLRs 3, 7, 8, and 9 mediators that enable immune cells to access the site of infection, collectively respond to nucleic acids from bacteria and viruses, as well as the responses of professional APCs essential for gen- and these intracellular family members induce the expression of erating effective adaptive immunity (1, 2). Primary triggers of type-1 IFNs that possess potent antiviral activities (11, 12). In by guest on September 28, 2021 inflammatory and adaptive responses are the TLRs, a family of contrast, TLRs 1, 2, 4, 5, and 6 sense outer membrane components cell surface innate immune sensors that exist in organisms ranging of bacteria, fungi, and protozoan organisms, and these receptors from lower invertebrates to higher mammals. Mammalian TLRs are expressed on the surface of mammalian cells. Although most alert the host to the presence of infection through direct recog- TLRs signal as homodimers, TLR2 requires TLR1 or TLR6 for nition of conserved structural components of viruses, bacteria, activity (13). TLR1/2 and TLR6/2 heterodimers discriminate fungi, and protozoans (3, 4). In addition to microbial and viral among different microbial products that include bacterial lip- products, TLRs sense molecules associated with damage to self- oproteins, bacterial lipoteichoic acids, nonenteric bacterial LPSs, tissues as well as host products of inflammation (5). fungal phospholipomannans, protozoan GPI anchors, and myco- Humans possess 10 TLR family members (1–10), subsets of bacterial lipomannans and phosphatidylinositols (3). The cell which are expressed in leukocytes and the epithelial cells of surface TLRs engage a core signaling pathway, leading to the mucosal surfaces (6–8). In accordance with their role in host de- activation of NF-kB, AP-1, and other transcription factors that drive the production of proinflammatory chemokines, cytokines, and cell-adhesion molecules (14). x *Department of Microbiology, †Department of Biochemistry, and College of Med- Despite extensive research on the TLRs, human TLR10 has icine, University of Illinois, Urbana, IL 61801; and ‡Center for Molecular Biophys- ics, Oak Ridge National Laboratory, Oak Ridge, TN 37831 remained an orphan receptor without a known agonist or function. TLR10 was initially cloned in 2001 and shares the greatest ho- Received for publication June 15, 2009. Accepted for publication February 18, 2010. mology with TLR1 and TLR6 (15). In mammals, TLR 10, 1, and 6 This work was supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant AI052344 (to R.I.T.). genes are tandemly arranged and seem to have arisen from du- Address correspondence and reprint requests to Dr. Richard Tapping, Department of plication events. Phylogeny supports the idea that TLR10 arose Microbiology, University of Illinois, B103 CLSL MC110, 601 South Goodwin Av- before the gene duplication that generated TLR1 and TLR6 (16, enue, Urbana, IL 61801. E-mail address: [email protected] 17). Chickens possess two TLRs that share ancestral origins with The online version of this article contains supplemental material. the TLR1-6-10 cluster and two additional TLRs that share origins Abbreviations used in this paper: ECD, extracellular domain; HA, hemagglutinin; with TLR2 (18). The fact that these chicken TLRs mediate re- HKAL, heat-killed Acholeplasma laidlawii; HKSA, heat-killed Staphylococcus sponses to lipopeptides through cooperative interactions indicates aureus; LTA-SA, lipoteichoic acid from S. aureus; LRR, leucine-rich repeat; Malp-2, macrophage-activating lipopeptide-2; MEF, murine embryonic fibroblast; PamCSK4, that this recognition function predates the mammalian expansion S-[2,3-bis(hydroxy)-propyl]-(R)-cysteinyl-(lysyl)3-lysine; Pam3CSK4, N-palmitoyl- of the TLR1-6-10 cluster (19). The TLR2 subfamily is thought to S-[2,3-bis(palmitoyloxy)-propyl]-(R)-cysteinyl-(lysyl)3-lysine; PamCysPamSK4, N- palmitoly-S-[2-hydroxy-3-(palmitoyloxy)propyl]-(R)-cysteinyl-(lysyl)3-lysine; P.G. have evolved under positive and balancing selection and, among LPS, Porphyromonas gingivalis LPS; TIR, Toll/IL-1R; TM, transmembrane. primates, Toll/IL-1R (TIR) domains seem to have undergone www.jimmunol.org/cgi/doi/10.4049/jimmunol.0901888 The Journal of Immunology 5095 purifying selection (20, 21). The independent maintenance of veloped by Jin et al. (25, 26). In short, a truncated portion of the TLR TLR10 and its associated TIR domain suggest a distinct biological ectodomain lacking the C-terminal cap was fused to the highly conserved role for this receptor (16, 19). LRR C-terminal capping module of VLRB.61, a hagfish variable lym- phocyte receptor. With the aid of the computer software DNAWorks TLR10 is an unusual family member in that it is highly expressed (Bethesda, MD) (27), six adjacent sets of ∼60-bp overlapping oligonu- in the B cell lineage, suggesting that it plays a critical role in B cell cleotides were used to synthesize the sequence encoding aa 133–200 of the function. The presence of sequence gaps and retroviral insertions hagfish VLRB.61 clone. Using overlap extension PCR, the VLR coding 9 reveals that mouse TLR10 is a pseudogene, a situation that pre- region was fused to the 3 -end of TLR 1, 2, and 10 ECD, encompassing aa 22–476, 17–508, and 20–474, respectively. The PCR products were cloned cludes the generation and phenotypic assessment of a TLR10 as a BglII/NheI fragment into a modified pDisplay vector containing an knock-out mouse. In this article, we report that human TLR10 HA-tag upstream of the BglII site and an Fc domain of the human IgG1 shares a variety of agonists with TLR1, including a number of cell- downstream of the NheI site (kindly provided by Dr. David M. Kranz, surface components of bacteria and fungi. Similar to TLR1 and Department of Biochemistry, University of Illinois at Urbana Champaign). 9 TLR6, TLR10 requires TLR2 for recognition. However, we found A thrombin cleavage site (LVPRGS) was also added at the 3 -end of the TLRvlr hybrid to allow cleavage of the soluble TLR from the Fc fusion that TLR10 lacks the downstream signaling typically associated protein. A Flag-tagged TLR2vlr-Fc construct was also engineered. with other TLR2 family members. TLR10 mutants. Site-directed mutagenesis of the TLR10 mutants was performed in TLR10 chimeric receptor TLR10-1.
Load more

Recommended publications
  • TLR3-Dependent Activation of TLR2 Endogenous Ligands Via the Myd88 Signaling Pathway Augments the Innate Immune Response
    cells Article TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response 1 2, 1 3 Hellen S. Teixeira , Jiawei Zhao y, Ethan Kazmierski , Denis F. Kinane and Manjunatha R. Benakanakere 2,* 1 Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] (H.S.T.); [email protected] (E.K.) 2 Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] 3 Periodontology Department, Bern Dental School, University of Bern, 3012 Bern, Switzerland; [email protected] * Correspondence: [email protected] Present address: Department of Pathology, Wayne State University School of Medicine, y 541 East Canfield Ave., Scott Hall 9215, Detroit, MI 48201, USA. Received: 30 June 2020; Accepted: 12 August 2020; Published: 17 August 2020 Abstract: The role of the adaptor molecule MyD88 is thought to be independent of Toll-like receptor 3 (TLR3) signaling. In this report, we demonstrate a previously unknown role of MyD88 in TLR3 signaling in inducing endogenous ligands of TLR2 to elicit innate immune responses. Of the various TLR ligands examined, the TLR3-specific ligand polyinosinic:polycytidylic acid (poly I:C), significantly induced TNF production and the upregulation of other TLR transcripts, in particular, TLR2. Accordingly, TLR3 stimulation also led to a significant upregulation of endogenous TLR2 ligands mainly, HMGB1 and Hsp60. By contrast, the silencing of TLR3 significantly downregulated MyD88 and TLR2 gene expression and pro-inflammatory IL1β, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1β, TNF and IL8, thus suggesting MyD88 / to somehow act downstream of TLR3.
    [Show full text]
  • Maturation and Is Inhibited by TLR2 Signaling Through TLR4 Promotes
    Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR2 This information is current as Elize A. Hayashi, Shizuo Akira and Alberto Nobrega of September 28, 2021. J Immunol 2005; 174:6639-6647; ; doi: 10.4049/jimmunol.174.11.6639 http://www.jimmunol.org/content/174/11/6639 Downloaded from References This article cites 45 articles, 26 of which you can access for free at: http://www.jimmunol.org/content/174/11/6639.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Role of TLR in B Cell Development: Signaling through TLR4 Promotes B Cell Maturation and Is Inhibited by TLR21 Elize A. Hayashi,* Shizuo Akira,† and Alberto Nobrega2* The role of TLR4 in mature B cell activation is well characterized.
    [Show full text]
  • Genetic Variation of the Toll-Like Receptors in a Swedish Allergic Rhinitis Case Population
    http://www.diva-portal.org This is the published version of a paper published in BMC Medical Genetics. Citation for the original published paper (version of record): Henmyr, V., Carlberg, D., Manderstedt, E., Lind-Halldén, C., Säll, T. et al. (2017) Genetic variation of the toll-like receptors in a Swedish allergic rhinitis case population. BMC Medical Genetics, 18(1): 18 https://doi.org/10.1186/s12881-017-0379-6 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:hkr:diva-16592 Henmyr et al. BMC Medical Genetics (2017) 18:18 DOI 10.1186/s12881-017-0379-6 RESEARCHARTICLE Open Access Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population V. Henmyr1,2*†, D. Carlberg2†, E. Manderstedt1,2, C. Lind-Halldén2, T. Säll1, L. O. Cardell3 and C. Halldén2 Abstract Background: Variation in the 10 toll-like receptor (TLR) genes has been significantly associated with allergic rhinitis (AR) in several candidate gene studies and three large genome-wide association studies. These have all investigated common variants, but no investigations for rare variants (MAF ≤ 1%) have been made in AR. The present study aims to describe the genetic variation of the promoter and coding sequences of the 10 TLR genes in 288 AR patients. Methods: Sanger sequencing and Ion Torrent next-generation sequencing was used to identify polymorphisms in a Swedish AR population and these were subsequently compared and evaluated using 1000Genomes and Exome Aggregation Consortium (ExAC) data.
    [Show full text]
  • CD Markers Are Routinely Used for the Immunophenotyping of Cells
    ptglab.com 1 CD MARKER ANTIBODIES www.ptglab.com Introduction The cluster of differentiation (abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules. So-called CD markers are routinely used for the immunophenotyping of cells. Despite this use, they are not limited to roles in the immune system and perform a variety of roles in cell differentiation, adhesion, migration, blood clotting, gamete fertilization, amino acid transport and apoptosis, among many others. As such, Proteintech’s mini catalog featuring its antibodies targeting CD markers is applicable to a wide range of research disciplines. PRODUCT FOCUS PECAM1 Platelet endothelial cell adhesion of blood vessels – making up a large portion molecule-1 (PECAM1), also known as cluster of its intracellular junctions. PECAM-1 is also CD Number of differentiation 31 (CD31), is a member of present on the surface of hematopoietic the immunoglobulin gene superfamily of cell cells and immune cells including platelets, CD31 adhesion molecules. It is highly expressed monocytes, neutrophils, natural killer cells, on the surface of the endothelium – the thin megakaryocytes and some types of T-cell. Catalog Number layer of endothelial cells lining the interior 11256-1-AP Type Rabbit Polyclonal Applications ELISA, FC, IF, IHC, IP, WB 16 Publications Immunohistochemical of paraffin-embedded Figure 1: Immunofluorescence staining human hepatocirrhosis using PECAM1, CD31 of PECAM1 (11256-1-AP), Alexa 488 goat antibody (11265-1-AP) at a dilution of 1:50 anti-rabbit (green), and smooth muscle KD/KO Validated (40x objective). alpha-actin (red), courtesy of Nicola Smart. PECAM1: Customer Testimonial Nicola Smart, a cardiovascular researcher “As you can see [the immunostaining] is and a group leader at the University of extremely clean and specific [and] displays Oxford, has said of the PECAM1 antibody strong intercellular junction expression, (11265-1-AP) that it “worked beautifully as expected for a cell adhesion molecule.” on every occasion I’ve tried it.” Proteintech thanks Dr.
    [Show full text]
  • TLR9 Gene Transcriptional Regulation of the Human
    Transcriptional Regulation of the Human TLR9 Gene Fumihiko Takeshita, Koichi Suzuki, Shin Sasaki, Norihisa Ishii, Dennis M. Klinman and Ken J. Ishii This information is current as of September 30, 2021. J Immunol 2004; 173:2552-2561; ; doi: 10.4049/jimmunol.173.4.2552 http://www.jimmunol.org/content/173/4/2552 Downloaded from References This article cites 49 articles, 31 of which you can access for free at: http://www.jimmunol.org/content/173/4/2552.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 30, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Transcriptional Regulation of the Human TLR9 Gene1 Fumihiko Takeshita,2* Koichi Suzuki,† Shin Sasaki,‡ Norihisa Ishii,‡ Dennis M. Klinman,* and Ken J. Ishii3* To clarify the molecular basis of human TLR9 (hTLR9) gene expression, the activity of the hTLR9 gene promoter was charac- terized using the human myeloma cell line RPMI 8226.
    [Show full text]
  • TLR Signaling Pathways
    Seminars in Immunology 16 (2004) 3–9 TLR signaling pathways Kiyoshi Takeda, Shizuo Akira∗ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Abstract Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing spe- cific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling. © 2003 Elsevier Ltd. All rights reserved. Keywords: TLR; Innate immunity; Signal transduction; TIR domain 1. Introduction 2. Toll-like receptors Toll receptor was originally identified in Drosophila as an A mammalian homologue of Drosophila Toll receptor essential receptor for the establishment of the dorso-ventral (now termed TLR4) was shown to induce the expression pattern in developing embryos [1]. In 1996, Hoffmann and of genes involved in inflammatory responses [3]. In addi- colleagues demonstrated that Toll-mutant flies were highly tion, a mutation in the Tlr4 gene was identified in mouse susceptible to fungal infection [2]. This study made us strains that were hyporesponsive to lipopolysaccharide [4]. aware that the immune system, particularly the innate im- Since then, Toll receptors in mammals have been a major mune system, has a skilful means of detecting invasion by focus in the immunology field.
    [Show full text]
  • Original Article Investigation for the Roles of TLR2, TLR9 and Th17/Treg in the Pathogenesis of Infectious Mononucleosis
    Int J Clin Exp Med 2017;10(10):14946-14953 www.ijcem.com /ISSN:1940-5901/IJCEM0037168 Original Article Investigation for the roles of TLR2, TLR9 and Th17/Treg in the pathogenesis of infectious mononucleosis Aning Gao1, Yawang Shao2 1Department of Pediatrics, The Central Hospital of Xianyang, Shaanxi Province, China; 2Department of Pediatrics, The First People’ s Hospital of Xianyang, Xianyang City 712000, Shaanxi Province, China Received August 3, 2016; Accepted August 12, 2017; Epub October 15, 2017; Published October 30, 2017 Abstract: Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV) infection. Toll-like receptor 2 (TLR2) has most recognized ligands, and is possibly direct receptor for anti-EBV. EBV can also activate TLR9 on B cells for inducing anti-viral response. T helper cell 17 (Th17) can promote inflammation by secreting IL-17, and is possibly involved in IM pathogenesis. Regulatory T cell (Treg) is a T cell sub-population with immune suppression. The previ- ous study has indicated insufficient Treg cell immunity for acute IM onset. This study thus aims to investigate the TLR2, TL9, Th17 and CD4+CD25+Treg cell expression, and to explore its potential role in IM. A total of 98 acute IM children and 76 IM children at recovery period were recruited in our hospital, in parallel with 52 healthy children. The qRT-PCR and western blot assay were used to test mRNA or protein expressions of TLR2 and TLR9, respectively. Flow cytometry was used to test percentage of Th17 and CD4+CD25+Foxp3+T cell in total CD4+T cells. ELISA was employed for detecting serum levels of IL-17, IL-22, IL-19 and TGF-β.
    [Show full text]
  • TLR2 Signaling Pathway Combats Streptococcus Uberis Infection by Inducing Mitochondrial Reactive Oxygen Species Production
    cells Article TLR2 Signaling Pathway Combats Streptococcus uberis Infection by Inducing Mitochondrial Reactive Oxygen Species Production 1, 1, 1 1,2 1 2 Bin Li y, Zhixin Wan y, Zhenglei Wang , Jiakun Zuo , Yuanyuan Xu , Xiangan Han , Vanhnaseng Phouthapane 3 and Jinfeng Miao 1,* 1 MOE Joint International Research Laboratory of Animal Health and Food Safty, Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; [email protected] (B.L.); [email protected] (Z.W.); [email protected] (Z.W.); [email protected] (J.Z.); [email protected] (Y.X.) 2 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China; [email protected] 3 Biotechnology and Ecology Institute, Ministry of Science and Technology (MOST), Vientiane 22797, Laos; [email protected] * Correspondence: [email protected]; Fax: +86-25-8439-8669 These authors contributed equally to this work. y Received: 6 January 2020; Accepted: 19 February 2020; Published: 21 February 2020 Abstract: Mastitis caused by Streptococcus uberis (S. uberis) is a common and difficult-to-cure clinical disease in dairy cows. In this study, the role of Toll-like receptors (TLRs) and TLR-mediated signaling pathways in mastitis caused by S. uberis was investigated using mouse models and mammary / epithelial cells (MECs). We used S. uberis to infect mammary glands of wild type, TLR2− − and / TLR4− − mice and quantified the adaptor molecules in TLR signaling pathways, proinflammatory cytokines, tissue damage, and bacterial count. When compared with TLR4 deficiency, TLR2 deficiency induced more severe pathological changes through myeloid differentiation primary response 88 (MyD88)-mediated signaling pathways during S.
    [Show full text]
  • Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods
    pharmaceutics Review Toll-Like Receptors and Relevant Emerging Therapeutics with Reference to Delivery Methods Nasir Javaid, Farzana Yasmeen and Sangdun Choi * Department of Molecular Science and Technology, Ajou University, Suwon 16499, Korea * Correspondence: [email protected]; Tel.: +82-31-219-2600 Received: 9 July 2019; Accepted: 28 August 2019; Published: 1 September 2019 Abstract: The built-in innate immunity in the human body combats various diseases and their causative agents. One of the components of this system is Toll-like receptors (TLRs), which recognize structurally conserved molecules derived from microbes and/or endogenous molecules. Nonetheless, under certain conditions, these TLRs become hypofunctional or hyperfunctional, thus leading to a disease-like condition because their normal activity is compromised. In this regard, various small-molecule drugs and recombinant therapeutic proteins have been developed to treat the relevant diseases, such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, systemic lupus erythematosus, and allergy. Some drugs for these diseases have been clinically approved; however, their efficacy can be enhanced by conventional or targeted drug delivery systems. Certain delivery vehicles such as liposomes, hydrogels, nanoparticles, dendrimers, or cyclodextrins can be employed to enhance the targeted drug delivery. This review summarizes the TLR signaling pathway, associated diseases and their treatments, and the ways to efficiently deliver the drugs to a target site. Keywords: Toll-like receptor; immunological disease; therapeutic; drug delivery method 1. Introduction The immune system in an organism is the protective system combating pathogenic and/or abnormal conditions. Innate and adaptive immune systems are two basic components in vertebrates. Adaptive immunity is mediated by T and B lymphocytes with the help of their antigen-specific receptors that are encoded as a result of hypermutability and rearrangements in a genomic region of the organism.
    [Show full text]
  • Not Signaling Mechanisms of Innate Immune Sensing but Human Tlrs
    Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling This information is current as Yue Guan, Diana Rose E. Ranoa, Song Jiang, Sarita K. of September 26, 2021. Mutha, Xinyan Li, Jerome Baudry and Richard I. Tapping J Immunol 2010; 184:5094-5103; Prepublished online 26 March 2010; doi: 10.4049/jimmunol.0901888 http://www.jimmunol.org/content/184/9/5094 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/03/25/jimmunol.090188 Material 8.DC1 http://www.jimmunol.org/ References This article cites 74 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/184/9/5094.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Human TLRs 10 and 1 Share Common Mechanisms of Innate Immune Sensing but Not Signaling Yue Guan,* Diana Rose E.
    [Show full text]
  • NF-Κb Signaling and Its Relevance to the Treatment of Mantle Cell Lymphoma
    Balaji et al. Journal of Hematology & Oncology (2018) 11:83 https://doi.org/10.1186/s13045-018-0621-5 REVIEW Open Access NF-κB signaling and its relevance to the treatment of mantle cell lymphoma Swathi Balaji, Makhdum Ahmed, Elizabeth Lorence, Fangfang Yan, Krystle Nomie and Michael Wang* Abstract Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways. NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation.
    [Show full text]
  • Adjuvant Effect of the Novel TLR1/TLR2 Agonist Diprovocim Synergizes with Anti–PD-L1 to Eliminate Melanoma in Mice
    Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti–PD-L1 to eliminate melanoma in mice Ying Wanga, Lijing Sua, Matthew D. Morinb, Brian T. Jonesb, Yuto Mifuneb, Hexin Shia, Kuan-wen Wanga, Xiaoming Zhana, Aijie Liua, Jianhui Wanga, Xiaohong Lia, Miao Tanga, Sara Ludwiga, Sara Hildebranda, Kejin Zhouc,d, Daniel J. Siegwartc,d, Eva Marie Y. Morescoa, Hong Zhanga, Dale L. Bogerb, and Bruce Beutlera,1 aCenter for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; bDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; cSimmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by Dennis A. Carson, University of California, San Diego, La Jolla, CA, and approved July 2, 2018 (received for review June 28, 2018) Successful cancer immunotherapy entails activation of innate immune (MyD88,TRIF,TRAM,andMAL),kinases, and ubiquitin ligases receptors to promote dendritic cell (DC) maturation, antigen pre- to activate NF-κB and IRFs (12–14). These and other transcription sentation, up-regulation of costimulatory molecules, and cytokine factors induce the expression of thousands of genes that carry out secretion, leading to activation of tumor antigen-specific cytotoxic the innate immune response (15). Several nucleotide-based adju- T lymphocytes (CTLs). Here we screened a synthetic library of 100,000 vants such as TLR3 agonist poly I:C (9), TLR9 agonist CpG (16), compounds for innate immune activators using TNF production by and STING agonist cGAMP (6) have been reported to improve THP-1 cells as a readout.
    [Show full text]