DOCSLIB.ORG

Double-Stranded RNA Promotes CTL-Independent Tumor Cytolysis Mediated by Cd11b+Ly6g+ Intratumor Myeloid Cells Through the TICAM-1 Signaling Pathway

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Double-Stranded RNA Promotes CTL-Independent Tumor Cytolysis Mediated by Cd11b+Ly6g+ Intratumor Myeloid Cells Through the TICAM-1 Signaling Pathway Cell Death and Differentiation (2017) 24, 385–396 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/17 www.nature.com/cdd Double-stranded RNA promotes CTL-independent tumor cytolysis mediated by CD11b+Ly6G+ intratumor myeloid cells through the TICAM-1 signaling pathway Hiroaki Shime*,1, Misako Matsumoto1 and Tsukasa Seya1 PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b+Ly6G+ cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b+Ly6G+ cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model. PolyI:C-induced inhibition of tumor growth was attributed to caspase-8/3 cascade activation in tumor cells that occurred independently of CD8α+/CD103+ dendritic cells (DCs) and CTLs. CD11b+Ly6G+ cells was essential for the antitumor effect because depletion of CD11b+Ly6G+ cells totally abrogated tumor regression and caspase activation after polyI:C treatment. CD11b+Ly6G+ cells that had been activated with polyI:C showed cytotoxicity and inhibited tumor growth through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS). These responses were abolished in either Toll/interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1)− / − or interferon (IFN)-αβ receptor 1 (IFNAR1)− / − mice. Thus, our results suggest that polyI:C activates the TLR3/TICAM-1 and IFNAR signaling pathways in CD11b+Ly6G+ cells in tumors, thereby eliciting their antitumor activity, independent of those in CD8α+/ CD103+ DCs that prime CTLs. Cell Death and Differentiation (2017) 24, 385–396; doi:10.1038/cdd.2016.131; published online 11 November 2016 Immune cells are implicated in the regulation of tumor activates the melanoma differentiation-associated gene 5 growth.1,2 Myeloid-derived cells, such as macrophages and (MDA5)-mitochondrial antiviral-signaling protein (MAVS) path- dendritic cells (DCs), express Toll-like receptors (TLRs) and way that induces a systemic IFN/cytokine production.9 These participate in the formation of tumor-progressive or tumor- pathways are conserved in most myeloid cells. suppressive microenvironments in response to pattern- Myeloid-derived cells are abnormally accumulated in tumor- recognition receptor (PRR) stimuli. Intratumor myeloid cells bearing hosts. CD11b+Ly6G+ cells represent a population of phagocytose tumor debris containing tumor-associated anti- tumor-supporting myeloid cells in mice.10 They accumulate in gens (TAAs) to prime antigen-specific cytotoxic T lymphocytes tumors and blood/lymphoid organs and promote tumor growth, – (CTLs) together with released cytokines.2 Although CTLs are metastasis, angiogenesis, and immunosuppression.11 14 critical for tumor regression, tumor cells do not always CD11b+Ly6G+ cells are identified as granulocytic myeloid- generate neoantigens or present TAAs.3,4 Even under the derived suppressor cells (G-MDSCs) or as tumor-associated conditions where CTLs no longer participate in tumor neutrophils (TANs).10 G-MDSCs and TANs show morphologi- elimination, TLR ligands often induce a tumor-regressive cal and functional similarities to neutrophils.15 In patients, response. Therefore, a CTL-independent antitumor event neutrophil infiltration into a tumor is correlated with poor occurs via stimulation of TLRs in tumor-associated myeloid prognosis.16,17 cells during immunotherapy with TLR ligands. The mechanism G-MDSCs preferentially produce reactive oxygen species/ of this antitumor response remains largely undetermined. reactive nitrogen species (ROS/RNS) including hydrogen PolyI:C, a synthetic double-stranded RNA (dsRNA) analog, peroxide (H2O2) and peroxynitrite (PNT). PNT is responsible induces type-I interferon (IFN) production and fosters CD8α+/ for the suppression of T cell-mediated antitumor immunity by – CD103+ DC maturation, leading to tumor growth inhibition G-MDSCs.18 21 Consequently, these suppression mechan- mediated by natural killer (NK) cells and CTLs in mice.5,6 In isms enable tumor cells to escape tumor antigen-specific either case, polyI:C activates TLR3 in endosomes.7 TLR3 CTLs. However, emerging evidence has revealed that activates Toll/interleukin-1 receptor domain-containing adap- functionally polarized neutrophils induced by cytokines, tor molecule-1 (TICAM-1) that evokes the production of type-I chemokines, or growth factors inhibit tumor growth and IFNs and proinflammatory cytokines.8 PolyI:C additionally metastasis.22–24 CD11b+Ly6G+ cells, therefore, have both a 1Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan *Corresponding author: Hiroaki Shime, Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan. Tel: +81 11 706 8178; Fax: +81 11 706 8178; E-mail: [email protected] Abbreviations: TLR, Toll-like receptor; CTL, cytotoxic T lymphocyte; NK, natural killer; dsRNA, double-stranded RNA; TICAM-1, Toll/interleukin-1 receptor domain- containing adaptor molecule-1; IFN, interferon; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; G-MDSC, granulocytic MDSC; M-MDSC, monocytic MDSC; TAN, tumor-associated neutrophil; ROS, reactive oxygen species; RNS, reactive nitrogen species; TNF, tumor necrosis factor; WT, wild type Received 27.5.16; revised 07.9.16; accepted 06.10.16; Edited by L Zitvogel; published online 11.11.2016 Antitumor CD11b+Ly6G+ cells induced by dsRNA H Shime et al 386 positive and negative impact on tumor growth that can be induces apoptosis of EL4 tumor cells through the caspase- determined by external stimuli. CD11b+Ly6G+ cells may act as 8/3 cascade, resulting in tumor growth inhibition. The TLR3/ a CTL-independent effector of tumor regression in response to TICAM-1 pathway triggers apoptosis in cancer cells through TLR ligands. caspase-8 activation.32 However, EL4 cells are insensitive to Tumor growth can be altered by targeting immunosuppres- direct stimulation with polyI:C.33 sive myeloid cells.25 Administration of ligands for TLR3 or TLR9 The polyI:C-induced caspase-3 activation in tumors induces a functional conversion of CD11b+Gr1+ MDSCs or occurred in Batf3− / − mice that lack CD8α+/CD103+ DC − – CD11b+Ly6G Ly6Chigh monocytic MDSCs (M-MDSCs).26 28 subsets34 (Supplementary Figure 1). Taken together, the We have previously demonstrated that a polyI:C-induced CD8α+/CD103+ DC-mediated NK and CTL induction is TLR3/TICAM-1 signal induces tumoricidal activity in tumor- unlikely involved in the inhibition of EL4 tumor growth. That associated macrophages (TAMs), leading to tumor growth is, previously unidentified cells and/or mechanisms could inhibition in 3LL tumor-bearing mice.29 In this study, using an participate in the therapeutic potential of polyI:C in the EL4- EL4 tumor model, we found that CD11b+Ly6G+ cells inhibit implant model. tumor growth upon polyI:C treatment even if tumor cells are out of targets of CTL, NK, and M1 TAM-mediated cytolysis. CD11b+Ly6G+ cells are essential for polyI:C-induced inhibition of EL4 tumor growth in mice. We ultimately + Results found that depletion of Gr1 cells abolished the polyI: C-induced inhibition of tumor growth (Figure 2a). Gr1 is a Inhibition of tumor growth by polyI:C treatment through common epitope of both Ly6G and Ly6C that are highly the TICAM-1 signaling pathway. The growth of EL4 tumors expressed on G-MDSCs/TAN and M-MDSCs, respectively. in mice was significantly retarded by polyI:C administration Treatment of tumor-bearing mice with an Ly6G-specific Ab (Figure 1a). To analyze the host signaling pathway involved in (1A8) almost completely abrogated both of the polyI: this tumor growth inhibition, EL4 cells were implanted into C-induced events: tumor growth inhibition and caspase-8/3 + mice deficient for TICAM-1 or MAVS that are downstream activation in tumors (Figures 2b and c). Ly6G cells adapter molecules of TLR3 or MDA5, respectively. The polyI: coexpressed CD11b (Supplementary Figure 2). Hence, + + C-induced inhibition of tumor growth was abrogated in CD11b Ly6G cells are responsible for the inhibition of EL4 TICAM-1− / − but not MAVS− / − mice (Figure 1a). PoyI:C tumor growth in polyI:C-treated mice. induces type-I IFN production, and the inhibition of EL4 tumor growth was abrogated in IFNAR1− / − mice. Thus, polyI:C PolyI:C-activated CD11b+Ly6G+ cells inhibit tumor treatment led to the inhibition of EL4 tumor growth via the growth. We analyzed the gene expression profile of TLR3/TICAM-1 and type-I IFN signaling pathways. EL4 cells CD11b+Ly6G+ cells isolated from tumor-bearing mice. express MHC class-I (H-2Db and H-2Kb), CD3ε, CD28, PD-1, IFN-α/β were upregulated in CD11b+Ly6G+ cells in response and PD-L1, but not MHC class-II (I-Ab), CD4, CD8, CD11b, to 4 h of polyI:C treatment, an effect that was abrogated in − − CD11c, and CTLA-4 (Supplementary Table 1). EG7 cells TICAM-1 / CD11b+Ly6G+ cells, whereas mRNA expression expressing a model TAA (OVA protein) are a CTL-sensitive of neither tumor-supporting factors such as arginase-1 cell line derived from EL4 cells. However, polyI:C-induced (Arg-1) nor vascular endothelial growth factor A (VEGFA) inhibition of EL4 tumor growth was not abrogated by were altered (Supplementary Figure 3a). Therefore, pretreatment of mice with antibodies (Abs) against CD8β, CD11b+Ly6G+ cells respond to polyI:C in vivo within 4 h to CD4, or NK1.1 (Figure 1b). alter their function. PolyI:C treatment robustly increased TUNEL (terminal CD11b+Gr1+ cells isolated from tumor-bearing mice deoxynucleotidyl transferase-mediated nick end labeling)- promote tumor growth when co-injected with tumor cell – positive cells, suggesting that apoptosis or necrosis occurred lines.35 37 Thus, we tested whether polyI:C-activated in the tumor (Figure 1c).
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]
  • Regulation of Neuronal Morphogenesis and Brain Functions Via Toll-Like Receptors Chiung-Ya Chen*, Yi-Chun Shih, Yun-Fen Hung and Yi-Ping Hsueh*
    Chen et al. Journal of Biomedical Science (2019) 26:90 https://doi.org/10.1186/s12929-019-0584-z REVIEW Open Access Beyond defense: regulation of neuronal morphogenesis and brain functions via Toll-like receptors Chiung-Ya Chen*, Yi-Chun Shih, Yun-Fen Hung and Yi-Ping Hsueh* Abstract Toll-like receptors (TLRs) are well known as critical pattern recognition receptors that trigger innate immune responses. In addition, TLRs are expressed in neurons and may act as the gears in the neuronal detection/alarm system for making good connections. As neuronal differentiation and circuit formation take place along with programmed cell death, neurons face the challenge of connecting with appropriate targets while avoiding dying or dead neurons. Activation of neuronal TLR3, TLR7 and TLR8 with nucleic acids negatively modulates neurite outgrowth and alters synapse formation in a cell-autonomous manner. It consequently influences neural connectivity and brain function and leads to deficits related to neuropsychiatric disorders. Importantly, neuronal TLR activation does not simply duplicate the downstream signal pathways and effectors of classical innate immune responses. The differences in spatial and temporal expression of TLRs and their ligands likely account for the diverse signaling pathways of neuronal TLRs. In conclusion, the accumulated evidence strengthens the idea that the innate immune system of neurons serves as an alarm system that responds to exogenous pathogens as well as intrinsic danger signals and fine-tune developmental processes of neurons. Keywords: Innate immunity, TLR, Neuronal development Introduction innate immune system responds quickly to danger sig- Organisms have host defense systems, namely adaptive nals and lacks antigen specificity.
    [Show full text]
  • FAS (CD95) Mediates Noncanonical IL-1 Β and IL-18 Maturation Via Caspase-8 in an RIP3-Independent Manner This Information Is Current As of September 26, 2021
    Cutting Edge: FAS (CD95) Mediates Noncanonical IL-1 β and IL-18 Maturation via Caspase-8 in an RIP3-Independent Manner This information is current as of September 26, 2021. Lukas Bossaller, Ping-I Chiang, Christian Schmidt-Lauber, Sandhya Ganesan, William J. Kaiser, Vijay A. K. Rathinam, Edward S. Mocarski, Deepa Subramanian, Douglas R. Green, Neal Silverman, Katherine A. Fitzgerald, Ann Marshak-Rothstein and Eicke Latz Downloaded from J Immunol 2012; 189:5508-5512; Prepublished online 9 November 2012; doi: 10.4049/jimmunol.1202121 http://www.jimmunol.org/content/189/12/5508 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2012/11/12/jimmunol.120212 Material 1.DC1 References This article cites 30 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/189/12/5508.full#ref-list-1 by guest on September 26, 2021 Why The JI? Submit online. • 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 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 © 2012 by The American Association of Immunologists, Inc. All rights reserved.
    [Show full text]
  • TLR3 Controls Constitutive IFN-Β Antiviral Immunity in Human Fibroblasts and Cortical Neurons
    TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons Daxing Gao, … , Jean-Laurent Casanova, Shen-Ying Zhang J Clin Invest. 2021;131(1):e134529. https://doi.org/10.1172/JCI134529. Research Article Immunology Infectious disease Graphical abstract Find the latest version: https://jci.me/134529/pdf The Journal of Clinical Investigation RESEARCH ARTICLE TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons Daxing Gao,1,2,3 Michael J. Ciancanelli,1,4 Peng Zhang,1 Oliver Harschnitz,5,6 Vincent Bondet,7 Mary Hasek,1 Jie Chen,1 Xin Mu,8 Yuval Itan,9,10 Aurélie Cobat,11,12 Vanessa Sancho-Shimizu,11,12,13 Benedetta Bigio,1 Lazaro Lorenzo,11,12 Gabriele Ciceri,5,6 Jessica McAlpine,5,6 Esperanza Anguiano,14 Emmanuelle Jouanguy,1,11,12 Damien Chaussabel,14,15,16 Isabelle Meyts,17,18,19 Michael S. Diamond,20 Laurent Abel,1,11,12 Sun Hur,8 Gregory A. Smith,21 Luigi Notarangelo,22 Darragh Duffy,7 Lorenz Studer,5,6 Jean-Laurent Casanova,1,11,12,23,24 and Shen-Ying Zhang1,11,12 1St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA. 2Department of General Surgery, The First Affiliated Hospital of USTC, and 3Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. 4Turnstone Biologics, New York, New York, USA.
    [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]
  • Human Cancer Cells TLR3 Can Directly Trigger Apoptosis In
    TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells Bruno Salaun, Isabelle Coste, Marie-Clotilde Rissoan, Serge J. Lebecque and Toufic Renno This information is current as of September 27, 2021. J Immunol 2006; 176:4894-4901; ; doi: 10.4049/jimmunol.176.8.4894 http://www.jimmunol.org/content/176/8/4894 Downloaded from References This article cites 44 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/176/8/4894.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 27, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TLR3 Can Directly Trigger Apoptosis in Human Cancer Cells1 Bruno Salaun,2 Isabelle Coste,2 Marie-Clotilde Rissoan, Serge J. Lebecque,3 and Toufic Renno TLRs function as molecular sensors to detect pathogen-derived products and trigger protective responses ranging from secretion of cytokines that increase the resistance of infected cells and chemokines that recruit immune cells to cell death that limits microbe spreading.
    [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]
  • Toll-Like Receptor 3 Is a Negative Regulator of Embryonic Neural Progenitor Cell Proliferation
    13978 • The Journal of Neuroscience, December 17, 2008 • 28(51):13978–13984 Brief Communications Toll-Like Receptor 3 Is a Negative Regulator of Embryonic Neural Progenitor Cell Proliferation Justin D. Lathia,1,2* Eitan Okun,1* Sung-Chun Tang,1,3* Kathleen Griffioen,1 Aiwu Cheng,1 Mohamed R. Mughal,1 Gloria Laryea,1 Pradeep K. Selvaraj,4 Charles ffrench-Constant,2,5 Tim Magnus,1,6 Thiruma V. Arumugam,1,4 and Mark P. Mattson1,7 1Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, 2Centre for Brain Repair and Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom, 3Department of Neurology, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin 640, Taiwan, 4Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, 5Medical Research Council Centre for Regenerative Medicine and Multiple Sclerosis Society Translational Research Centre, University of Edinburgh, Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom, 6Neurologische Universita¨tsklinik, Universita¨t Hamburg, 20246 Hamburg, Germany, and 7Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation.
    [Show full text]
  • TRAIL, Fas Ligand, TNF and TLR3 in Cancer, Resistance to Targeted Anti-Cancer Therapeutics, DOI 10.1007/978-3-319-56805-8 310 Index
    Index A Apoptosis Acid sphingomyelinase (aSMase), 230, 231, aberrant regulation, 81–82 233, 234, 236, 240 anti-tumor assay, 135 Activation-induced cell death (AICD), CD95 antagonists, 134 144–145 cIAP-1- and cIAP-2-molecular Acute lymphoblastic leukemia (ALL), 67 mechanism, 135 Acute respiratory distress syndrome clinical trials, 135 (ARDS), 139 control of, 80–81 Adoptive cell transfer (ACT), 145 cytochrome c and ATP, 134 Agonistic TRAIL-R2 antibody DR superfamily, 134 Drozitumab, 69 Krammer’s laboratory, 135 Ag-presenting cells (APCs) mitochondrion, 134 CD4+ Th cells, 132 non-apoptotic functions, 134 CD8+ cytotoxic lymphocytes, 132 non-apoptotic signalling Lpr and gld mice, 133 pathways, 135 MHC class II molecules, 131 PI3K signalling pathway, 135 non-self-Ags, 131 signalling pathways, 134 T-cell extravasation, 132 Apoptosome, 134 T-cells, 132 Apoptotic signalling, Fas/CD95 Th subset lineages, 132 CD74, 195–196 Aliphatic amino alcohol sphingoid c-FLIP, 191, 192 backbone, 230 chemotherapy and cancer 17-Allylamino-17-demethoxygeldanamycin anti-cancer drugs, 204–206 (17-AAG), 119 caspase-8, 207 ALPS. See Autoimmune lymphoproliferative cisplatin, 204 syndrome (ALPS) death receptors, 204 Amphipathic α helices, 257 edelfosine, 204, 207, 208 Anti-apoptosis antigen 1 (APO-1), 135 death receptor, 191 Antiapoptotic Bcl-2 proteins, 80, 83, 84 FAIM, 194 Anti-apoptotic factor BclxL, 144 FAP-1, 192–193 Anti-CD95 antibodies, 67 lipid rafts (see Lipid rafts, Fas/CD95) Anti-CD95-induced ceramide, 235 nucleolin, 194–195 Anti-CD95L antibodies, 137 proteins and signalling pathways, 192 Anti-ceramide antibodies, 233 Arginine N-GlcNAcylation, 266 Anti-GRP-78 antibody, 100 Arylquin-1, 103 © Springer International Publishing AG 2017 309 O.
    [Show full text]
  • In-Vitro Evaluation of Effects of Mesenchymal Stem Cells on TLR3, TLR7/8 and TLR9-Activated Natural Killer Cells
    DOI: 10.14744/ejmo.2021.15684 EJMO 2021;5(1):71–79 Research Article In-vitro Evaluation of Effects of Mesenchymal Stem Cells on TLR3, TLR7/8 and TLR9-activated Natural Killer Cells Alper Tunga Ozdemir,1 Cengiz Kirmaz,2 Rabia Bilge Ozgul Ozdemir,3 Papatya Degirmenci,4 Mustafa Oztatlici,5 Mustafa Degirmenci6 1Department of Medical Biochemistry, Merkezefendi State Hospital, Manisa, Turkey 2Department of Allergy and Clinical Immunology, Celal Bayar University Faculty of Medicine, Manisa, Turkey 3Department of Allergy and Clinical Immunology, Manisa City Hospital, Manisa, Turkey 4Department of Allergy and Clinical Immunology, Tepecik Training and Research Hospital, Izmir, Turkey 5Department of Histology and Embryology, Celal Bayar University Faculty of Medicine, Manisa, Turkey 6Department of Medical Oncology, Tepecik Training and Research Hospital, Izmir, Turkey Abstract Objectives: In this study, it was aimed to investigate the immunomodulatory effects of Mesenchymal stem cells (MSCs) on Natural Killer (NK) cells activated by Toll-like receptor (TLR) agonists. Methods: MDA-MB-231, MCF-7 and NK-92 cells were induced with TLR3, TLR7/8 and TLR9 agonists and co-cultured with MSCs. Alterations in IFN-γ, TNF-α, Granzyme-b and Perforin expressions were determined by qPCR method, CD69 and CD107a expressions were determined by flow cytometry, and cytotoxicity was determined by MTT-assay. Results: All TLR agonists significantly increased the expressions of the IFN-γ, TNF-α, Granzyme-b, Perforin, CD69 and CD107a in-vitro. We determined that the cytokine, cytotoxic molecules, and activation markers of NK-92 cells interact- ing with breast tumor cells significantly increased by TLR3 and TLR9 agonists. However, suppression rather than activa- tion occurred on the NK-92 cells due to the simultaneous induction of the immunosuppressive effects of MSCs by these agonists.
    [Show full text]
  • TLR3 Sensing of Viral Infection F
    The Open Infectious Diseases Journal, 2010, 4, 1-10 1 Open Access TLR3 Sensing of Viral Infection F. Dunlevy, N.G. McElvaney and C.M. Greene* Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland Abstract: Viral infection is detected by the innate immune system which mounts a rapid semi-selective defence involving inflammation and production of type 1 interferons. Several sensors, both cell surface and intracellular, exist to detect different types of viral motifs. Double-stranded RNA viruses and dsRNA replication intermediates are detected by toll- like receptor 3 (TLR3) as well as by retinoid-inducible gene 1 (RIG-I) like receptors. Binding of dsRNA or its synthetic analogue poly I:C to TLR3 recruits the adaptor protein TRIF and stimulates distinct pathways leading to activation of interferon regulatory factor (IRF) and NF-B. Here, we review the signalling cascades initiated by TLR3 and the modulation of these pathways. Keywords: TLR3, virus, dsRNA, signalling, type 1 interferons, NF-B. TLR3: SENSING OF VIRAL INFECTION TLR3 LIGANDS Human cells are equipped with a range of pattern- The ligand for TLR3 was identified as dsRNA relatively recognition receptors (PRRs) which recognise microbial recently in 2001 [1, 6]. Eight families of dsRNA viruses pathogen-associated molecular patterns (PAMPs), and mount exist including the rotaviruses which are implicated in infant innate immune responses following infection. Anti-viral mortality [7]. A further source of dsRNA is derived from the sensors can be broadly classified into two groups; toll-like replication of other RNA and DNA viruses which produce receptor family members and retinoid-inducible gene 1 dsRNA as a by-product of replication [8].
    [Show full text]
  • IL-24 Sensitizes Tumor Cells to TLR3-Mediated Apoptosis
    Cell Death and Differentiation (2013) 20, 823–833 & 2013 Macmillan Publishers Limited All rights reserved 1350-9047/13 www.nature.com/cdd IL-24 sensitizes tumor cells to TLR3-mediated apoptosis R Weiss1, M Sachet1, J Zinngrebe2, T Aschacher1, M Krainer3,4, B Hegedus1,4,5, H Walczak*,2 and M Bergmann*,1,4 Interleukin-24 (IL-24), a member of the IL-10 cytokine family whose physiological function remains largely unknown, has been shown to induce apoptosis when expressed in an adenoviral background. It is yet little understood, why IL-24 alone induced apoptosis only in a limited number of tumor cell lines. Analyzing an influenza A virus vector expressing IL-24 for its oncolytic potential revealed enhanced pro-apoptotic activity of the chimeric virus compared with virus or IL-24 alone. Interestingly, IL-24-mediated enhancement of influenza-A-induced apoptosis did not require viral replication but critically depended on toll-like receptor 3 (TLR3) and caspase-8. Immunoprecipitation of TLR3 showed that infection by influenza A virus induced formation of a TLR3-associated signaling complex containing TRIF, RIP1, FADD, cFLIP and pro-caspase-8. Co-administration of IL-24 decreased the presence of cFLIP in the TLR3-associated complex, converting it into an atypical, TLR3-associated death-inducing signaling complex (TLR3 DISC) that induced apoptosis by enabling caspase-8 activation at this complex. The sensitizing effect of IL-24 on TLR3-induced apoptosis, mediated by influenza A virus or the TLR3-specific agonist poly(I:C), was also evident on tumor spheroids. In conclusion, rather than acting as an apoptosis inducer itself, IL-24 sensitizes cancer cells to TLR-mediated apoptosis by enabling the formation of an atypical DISC which, in the case of influenza A virus or poly(I:C), is associated with TLR3.
    [Show full text]