Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373-384

Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Nature Immunology (Impact Factor: 20). 05/2010; 11(5):373-84. DOI: 10.1038/ni.1863
Source: PubMed


The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

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    • "Innate immunity serves as the first line of defense in the response against the pathogenic invasion of hosts by viruses. Such responses are usually initiated by the detection of viral nucleic acid via pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs) in the endosome and RIG-I-like receptors (RLRs) in the cytoplasm (Kawai & Akira, 2010; Takeuchi & Akira, 2010; Barbalat et al, 2011). TLR family members TLR3, 7, 8, and 9 detect endosomal DNA and RNA viruses, while RIG-I, MDA5, and LGP2 of the RLR family are the sensors specific for cytoplasmic RNA viruses (Nakhaei et al, 2009; O'Neill & Bowie, 2010; Kato et al, 2011). "
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    ABSTRACT: RIG-I is a well-studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4-Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG-I. The p97 complex is able to directly bind both non-ubiquitinated RIG-I and the E3 ligase RNF125, promoting K48-linked ubiquitination of RIG-I at residue K181. Viral infection significantly strengthens the interaction between RIG-I and the p97 complex by a conformational change of RIG-I that exposes the CARDs and through K63-linked ubiquitination of these CARDs. Disruption of the p97 complex enhances RIG-I antiviral signaling. Consistently, administration of compounds targeting p97 ATPase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus (VSV) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.
    The EMBO Journal 10/2015; DOI:10.15252/embj.201591888 · 10.43 Impact Factor
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    • "These structures are termed Pathogen-Associated Molecular Patterns (PAMPs) and are sensed by a limited number of so-called Pattern- Recognition Receptors (PRRs). One important class of PRRs is represented by the Toll-like receptor (TLR) family that is crucial for the triggering of the effector phase of the innate immune response [14] [15] [16]. TLR2 and TLR4, which are involved in Gram-positive and Gram-negative bacterial sensing, respectively, have been previously detected in the odontoblast cell membrane in healthy pulp, indicating that odontoblasts are equipped to recognize these pathogens when they diffuse through dentin tubules during the carious infection [13] [17]. "
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    ABSTRACT: Dental caries is a chronic infectious disease resulting from the penetration of oral bacteria into the enamel and dentin. Microorganisms subsequently trigger inflammatory responses in the dental pulp. These events can lead to pulp healing if the infection is not too severe following the removal of diseased enamel and dentin tissues and clinical restoration of the tooth. However, chronic inflammation often persists in the pulp despite treatment, inducing permanent loss of normal tissue and reducing innate repair capacities. For complete tooth healing the formation of a reactionary/reparative dentin barrier to distance and protect the pulp from infectious agents and restorative materials is required. Clinical and in vitro experimental data clearly indicate that dentin barrier formation only occurs when pulp inflammation and infection are minimised, thus enabling reestablishment of tissue homeostasis and health. Therefore, promoting the resolution of pulp inflammation may provide a valuable therapeutic opportunity to ensure the sustainability of dental treatments. This paper focusses on key cellular and molecular mechanisms involved in pulp responses to bacteria and in the pulpal transition between caries-induced inflammation and dentinogenic-based repair. We report, using selected examples, different strategies potentially used by odontoblasts and specialized immune cells to combat dentin-invading bacteria in vivo .
    Mediators of Inflammation 10/2015; 2015(Article ID 230251). DOI:10.1155/2015/230251 · 3.24 Impact Factor
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    • "Toll-like receptors (TLRs) serve as important pattern recognition receptors (PRR) and type I transmembrane proteins containing four typical motifs: a signal peptide (SP), an extracellular leucine-rich repeat (LRR) domain, a transmembrane domain (TM), and an intracellular Toll/IL-1 receptor (TIR) domain. The LRR domain recognizes conserved pathogen-associated molecular patterns (PAMPs) and TIR domain activates downstream signaling pathways [6] [7]. In mammal, several parasitic components serve as the ligands of the host TLRs. "
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    ABSTRACT: Toll-like receptors (TLR) are key components of innate immunity that play significant roles in immune defense against pathogens invasion. Recent frequent outbreaks of the "white spot disease" caused by parasitic infection in farmed Tibetan fishes had resulted in great economic losses. However, to our knowledge, the roles of TLRs in mediating immune response to parasitic infection in Tibetan fishes remain to be determined. Here, we performed data-mining on a widely-farmed Tibetan fish (Gymnocypris przewalskii or Gp) transcriptome to determine the genetic variation and expression pattern of TLRs. We totally obtained 14 GpTLRs and identified 5 with a complete coding sequence. Phylogenetic analysis verified their identities and supported the classification of TLRs into six families as in other vertebrates. The TLR family motifs, such as leucine rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain, are conserved in GpTLR1-5. Selective pressure test demonstrated that all known GpTLRs are under purifying selection, except GpTLR4 underwent positive selection. Further, site model analysis suggested that 11 positively selected sites are found in LRR domain of GpTLR4. Three positively selected sites are located on outside surface of TLR4 3D structure, indicating that function of GpTLR4 may be affected. Tissue specific expression analysis showed all GpTLRs are present in gill, head-kidney and spleen but the relative abundance varied among tissues. In response to parasite Ichthyophthirius multifiliis infection, 5 GpTLR (GpTLR1, -2, -4, -9 and -20) expressions were induced. Intriguingly, GpTLR4 was significantly up-regulated in gills, while GpTLR19 and GpTLR21 unexpectedly showed no any change. In summary, these results revealed the first genomic resources of TLR family and several parasitic infection responsive TLRs in Tibetan fish. These findings provide key information for future studies aiming to understand the molecular mechanisms underlying the immune response to pathogen invasion in Tibetan fishes. Copyright © 2015. Published by Elsevier Ltd.
    Fish &amp Shellfish Immunology 10/2015; 46(2):334–345. DOI:10.1016/j.fsi.2015.06.023 · 2.67 Impact Factor
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