Skip to content. Skip to navigation
Sections
Personal tools
You are here: Home
Featured Journal
Navigation
Site Search
 
Search only the current folder (and sub-folders)
Log in


Forgot your password?
New user?
Check out our New Publishers' Select for Free Articles
Journal Search

Advanced Drug Delivery Reviews (v.60, #7)

Editorial Board (pp. ii).
Toll-like receptor and pattern sensing for evoking immune response by Tsukasa Seya Theme Editor (pp. 779-781).

Nucleic acid-sensing Toll-like receptors: Beyond ligand search by Kensuke Miyake (pp. 782-785).
Nucleic acids from microbes were known to be immunogenic for a long time, but their sensors have been only recently identified. Two types of sensors, Toll-like receptors (TLR) and the RIG-I-like receptors (RLR), principally respond to nucleic acid. Discovery of these sensors have opened basic research as to how our immune system handles microbial nucleic acids. Recent results demonstrate that functional interaction between pathogen sensors is critically involved in the extent and type of immune responses. Moreover, responsiveness of nucleic acid-sensing TLRs is profoundly influenced by molecules associated with TLRs or with nucleic acids. Our understanding of mechanisms by which TLR responses were controlled would contribute to development of drugs such as immunostimulatory nucleic acids or small chemicals antagonizing TLRs.

Keywords: Toll-like receptors; RIG-I-like receptors; Nucleic acid


Toll-like receptors regulation of viral infection and disease by Joseph M. Thompson; Akiko Iwasaki (pp. 786-794).
In recent years, it has become increasingly evident that mammalian Toll-like receptors (TLRs) play a critical role in determining the outcome of virus infection. TLRs have evolved to recognize viral nucleic acids, and promote the stimulation of innate and adaptive immune responses. Interestingly, the study of mice harboring deficiencies in various TLR proteins and their adaptors suggests that TLR activation promotes protective anti-viral immunity in some cases, while exacerbating virus-induced disease in others. In this report we describe the interactions of viruses with both the TLR system and the intracellular recognition system and highlight the role of TLRs in shaping the outcome of virus infection in both a positive and negative manner.

Keywords: Innate immunity; Viral recognition; Viral pathogenesis; TLR; Pattern recognition receptor; Type I interferon


TLR9 as a key receptor for the recognition of DNA by Yutaro Kumagai; Osamu Takeuchi; Shizuo Akira (pp. 795-804).
Unmethylated DNA with CpG-motifs is recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Macrophages and conventional dendritic cells (cDCs) produce proinflammatory cytokines to B/K-type CpG-DNA, whereas plasmacytoid DCs induce type I interferons to A/D-type CpG-DNA and DNA viruses. The TLR9 mediated signaling pathway is not only responsible for activation of innate immune cells, but also for mounting acquired responses. Thus, it has been attempted to exploit TLR9 ligands as a vaccine adjuvant for anti-cancer immunotherapy. Further, TLR9 mediated signaling is implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. Nevertheless, recent studies revealed that double-stranded DNA can be recognized by intracellular receptor(s) in a TLR9-independent manner. This review will focus on the roles of TLR9 in immune responses, and its signaling pathways.

Keywords: Innate immunity; CpG-DNA; Cell signaling; Type I interferon; Plasmacytoid dendritic cell; Autoimmunity


TLR3: Interferon induction by double-stranded RNA including poly(I:C) by Misako Matsumoto; Tsukasa Seya (pp. 805-812).
Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA and its synthetic analog polyriboinosinic:polyribocytidylic acid (poly(I:C)) and induces type I interferon (IFN), inflammatory cytokine/chemokine production and dendritic cell (DC) maturation via the adaptor protein TICAM-1 (also called TRIF). TLR3 is expressed both intracellularly and on the cell surface of fibroblasts and epithelial cells, but is localized to the endosomal compartment of myeloid DCs. Several studies in TLR3-deficient mice demonstrate that TLR3 participates in the generation of protective immunity against some viral infections. Involvement of TLR3-TICAM-1 in activation of NK cells and CTLs by myeloid DCs suggests that TLR3 serves as an inducer of cellular immunity sensing viral infection rather than a simple IFN inducer. In this review, we summarize the current knowledge on TLR3 and discuss its possible role in innate and adaptive immunity.

Keywords: Adjuvant; Cross-priming; Double-stranded RNA; Innate immunity; NK cell activation; Toll-like receptor; Type I interferon; Viral infection


Recognition of viral single-stranded RNA by Toll-like receptors by Sandra S. Diebold (pp. 813-823).
The Toll-like receptors (TLR), mediating innate immune activation upon recognition of viral nucleic acids, represent promising targets for the development of adjuvants. Therefore, there is great interest in unraveling the underlying mechanisms of ligand recognition. Studies aiming to identify which sequences, nucleic acid modifications and molecular moieties of viral nucleic acids trigger or inhibit TLR activation have allowed insights into this subject, yet there are still many aspects of innate recognition of viral nucleic acids which are only partially understood. This review discusses our current understanding of TLR-mediated recognition of viral single-stranded RNA (ssRNA) by TLR7 and TLR8. Oligoribonucleotides (ORN) and small immune response modifiers such as imidazoquinolines with agonist function have served as tools to study ligand recognition. In addition, there is increasing evidence that TLR-mediated recognition of mammalian ssRNA triggers innate immune activation and plays a role in autoimmunity. Thus the development of suitable TLR7 and TLR8 antagonists could pave the way for therapeutic intervention of particular autoimmune diseases.

Keywords: Abbreviations; DC; dendritic cells; DAI; DNA-dependent activator of IFN-regulatory factors; dsRNA; double-stranded RNA; MDA5; melanoma differentiation-associated gene 5; PAMP; pathogen-associated molecular pattern; PDC; plasmacytoid DC; IFN-I; type I interferon; PRR; pattern recognition receptor; RIG-I; retinoic acid inducible gene I; ssRNA; single-stranded RNA; TLR; Toll-like receptor.Adjuvant; Dendritic cells; Immune response modifiers; Innate immunity; Pathogen-associated molecular patterns; Pattern recognition receptors; Toll-like receptors; Virus


Forward genetic analysis of TLR-signaling pathways: An evaluation by Kasper Hoebe; Bruce Beutler (pp. 824-829).
Forward genetic approaches have contributed to our understanding of how the host senses infectious agents such as bacteria, viruses and fungi. Beginning with the initial discovery of Toll-like receptors (TLRs) as primary sensors involved in the recognition of microbial components, our laboratory has taken a forward genetic approach, using N-ethyl- N-nitrosourea (ENU) mutagenesis in mice, to decipher TLR-signaling pathways. This long term effort has helped to elucidate the circuitry of these pathways, identified new molecules, and disclosed new functions for known molecules. Here we review some of the more important insights developed from this approach and discuss its prospects.

Keywords: ENU; Mutagenesis; TLR; Innate immunity


Intracellular pattern-recognition receptors by Catherine Dostert; Etienne Meylan; Jürg Tschopp (pp. 830-840).
The last ten years of research in the field of innate immunity have been incredibly fertile: the transmembrane Toll-like receptors (TLRs) were discovered as guardians protecting the host against microbial attacks and the emerging pathways characterized in detail. More recently, cytoplasmic sensors were identified, which are capable of detecting not only microbial, but also self molecules. Importantly, while such receptors trigger crucial host responses to microbial insult, over-activity of some of them has been linked to autoinflammatory disorders, hence demonstrating the importance of tightly regulating their actions over time and space. Here, we provide an overview of recent findings covering this area of innate and inflammatory responses that originate from the cytoplasm.

Keywords: Innate immunity; Intracellular PRRs; Inflammation; Virus recognition


Cytoplasmic recognition of RNA by Mitsutoshi Yoneyama; Koji Onomoto; Takashi Fujita (pp. 841-846).
Non-self RNA appearing in a cell as a result of viral replication is detected by a cytoplasmic sensor called RIG-I-like receptor (RLR). RLR consists of RIG-I, MDA5, and LGP2, which are DExD/H helicases. Domain structures of RLR for detecting non-self RNA and for relaying signals downstream have been elucidated. Different viruses produce structurally different RNA species and are sensed differentially by RLR molecules to initiate antiviral responses and subsequent antigen-specific adaptive immunity.

Keywords: Interferon; RLR; dsRNA; Viral RNA; Self-non-self recognition


Cytosolic DNA recognition for triggering innate immune responses by Akinori Takaoka; Tadatsudu Taniguchi (pp. 847-857).
The detection of microbial components by pattern recognition receptors (PRRs) and the subsequent triggering of innate immune responses constitute the first line of defense against infections. Recently, much attention has been focused on cytosolic nucleic acid receptors; the activation of these receptors commonly evokes a robust innate immune response, the hallmark of which is the induction of type I interferon (IFN) genes. In addition to receptors for RNA, receptors that detect DNA exposed in the cytosol and activate innate immune responses have long been thought to exist. Recently, DAI (DLM-1/ZBP1) has been identified as a candidate cytosolic DNA sensor. Cytosolic signaling by DNA-activated DAI (DLM-1/ZBP1) signaling results in activation of the two pathways of gene transcription critical to innate immune responses, the IRF and NF-κB pathways. In this review, we summarize our current view of activation mechanism and immunological roles of DAI (DLM-1/ZBP1) and related molecules. In addition, we also discuss the issue of self vs. non-self DNA recognition by DAI (DLM-1/ZBP1) and other DNA sensors in terms of the possible involvement in autoimmune abnormalities.

Keywords: Innate immunity; DNA; Pattern recognition receptor; DAI (DLM-1/ZBP1); Interferon-regulatory factor
Featured Book
Web Search
Powered by Plone CMS, the Open Source Content Management System

This site conforms to the following standards: