Bifurcation of Toll-Like Receptor 9 Signaling by Adaptor Protein 3

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Science (Impact Factor: 33.61). 09/2010; 329(5998):1530-4. DOI: 10.1126/science.1187029
Source: PubMed


Endosomal Toll-like receptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclear
factor κB (NF-κB)–dependent proinflammatory cytokines and interferon regulatory factor 7 (IRF7)–dependent type I interferons
(IFNs). Recognition of viral nucleic acids by TLR9 requires its cleavage in the endolysosomal compartment. Here, we show that
TLR9 signals leading to the activation of type I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from
endosomes to a specialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the protein complex responsible
for the trafficking of TLR9 to this subcellular compartment. Our results reveal an intracellular mechanism for bifurcation
of TLR9 signals by selective receptor trafficking within the endosomal system.

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Available from: Melissa M Linehan, Sep 30, 2015
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    • "EP67 is a C5a receptor agonist, which like CpG ODN is capable of inducing a proinflammatory environment [41]. The types of immune responses induced by CpG ODNs depend on their structural features which determines differences in their uptake and intracellular internalization [42] [43] [44]. We selected the type B CpG ODN because of the reports that this ODN type not only can activate humoral immunity (B-cells) but also is a strong inducer of nuclear factor (NF-kB) signaling (a critical transcription factor) and production of cytokines involved in the activation of multiple cell populations [42] [43] including bone cells such as osteoblasts [45]. "
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    ABSTRACT: TLR-9 ligand CpG oligodeoxynucleotide type B (CpG ODN) induces a proinflammatory environment. We evaluated effects of a preoperative CpG ODN application in an implant-associated Staphylococcus aureus bone infection model by monitoring bacterial loads and cytokine and chemokine levels. A total of 95 rats were used in four different groups: CpG ODN group (group 1; n=25), non-CpG-ODN group (group 2; n=25); saline pretreatment (group 3; n=25), and one uninfected group (group 4; n=20). A single dose of CpG-ODN was administered to the left tibialis anterior muscle 3 days prior to surgery and the tibia midshaft was osteotomized, stabilized by an intramedullary implant and subsequently contaminated with 10(3) colony forming units (CFUs) of Staphylococcus aureus in group 1-3. The osteotomy gap in animals of group 4 was not contaminated with S. aureus and those animals did not receive any pretreatment. CpG ODN administration resulted in significant reduction of the bacterial load in tibia tissue homogenate and on the implant surface on day 1 post-infection compared to non-CpG-ODN pretreatment (p<0.05; p<0.05). Reductions in bacterial CFUs, compared to non-treated (saline) controls, were approximately 67% and 77 % for bone tissue homogenates and implants. No bacteria were detected in uninfected rats. Early reduction of bacterial CFUs in the tibia was accompanied by increased levels of proinflammatory mediators MIP-2, IL-1β and RANTES in bone tissue milieu of the CpG ODN treated group compared to controls. At day 42 post infection, bone marrow tissue of rats pretreated with CpG ODN had comparable high bacterial CFU numbers as the non CpG ODN or saline treated groups. Microbiological analysis of implants removed from CpG ODN treated rats showed high bacterial growth densities on their surfaces which were not different from those observed in controls. In histology, all animals of group 1-3 showed established infected non-unions. Additionally, inflammatory mediator profiles in bone marrow homogenates of CpG ODN treated rats resembled those seen in infected controls. In this rat model, prophylactic administration of a single dose of CpG ODN, resulted in marked reduction of S. aureus load in the infected tibia during the initial stage of infection but failed to prevent development of chronic infection over time. Copyright © 2015. Published by Elsevier Inc.
    Bone 05/2015; 78. DOI:10.1016/j.bone.2015.04.030 · 3.97 Impact Factor
    • "(see colour version of this figure at demonstrated to be essential for trafficking TLR9 from the cell surface to the endosome (Lee et al., 2013; Sasai et al., 2010). As well as delivery at the correct location, the endosomal TLRs also require acidification of the endosome. "
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    ABSTRACT: As we learn more about the biology of the Toll-like receptors (TLRs), a wide range of molecules that can activate this fascinating family of pattern recognition receptors emerges. In addition to conserved pathogenic components, endogenous danger signals created upon tissue damage are also sensed by TLRs. Detection of these types of stimuli results in TLR mediated inflammation that is vital to fight pathogenic invasion and drive tissue repair. Aberrant activation of TLRs by pathogenic and endogenous ligands has also been linked with the pathogenesis of an increasing number of infectious and autoimmune diseases, respectively. Most recently, allergen activation of TLRs has also been described, creating a third broad class of TLR stimulus that has helped to shed light on the pathogenesis of allergic disease. To date, microbial activation of TLRs remains best characterized. Each member of the TLR family senses a specific subset of pathogenic ligands, pathogen associated molecular patterns (PAMPS), and a wealth of structural and biochemical data continues to reveal the molecular mechanisms of TLR activation by PAMPs, and to demonstrate how receptor specificity is achieved. In contrast, the mechanisms by which endogenous molecules and allergens activate TLRs remain much more mysterious. Here, we provide an overview of our current knowledge of how very diverse stimuli activate the same TLRs and the structural basis of these modes of immunity.
    Critical Reviews in Biochemistry and Molecular Biology 04/2015; DOI:10.3109/10409238.2015.1033511 · 7.71 Impact Factor
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    • "Disruption of TLR9 movement in either of these two trafficking pathways by eliminating LC3 or AP-3 results in blocking IFN induction without blocking the production of inflammatory cytokines (Sasai et al., 2010). Although the work published primarily focused on TLR9, some work with TLR3 and 7 ligands in the endocytic pathway suggest that they may be regulated similarly (Sasai et al., 2010). TLR3, 7, 8 and 9 all induce type-I IFNs in plasmacytoid dendritic cells where they are expressed, but the signaling molecules downstream differ between TLR3 and the others. "
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    ABSTRACT: To prevent the spread of infection, an invading pathogen must first be recognized by the innate immune system. Host pattern recognition receptors detect distinct pathogen-associated molecules and induce the transcription and release of interferon and inflammatory molecules to resolve infection. Unlike infections with pathogens that replicate autonomously from the host, viral infections blur the boundaries of self and non-self. Differentiation of host from virus is achieved by restricting localization of host nucleic acids and by placing pattern recognition receptors in specific subcellular compartments. Within this review, we discuss how several families of pattern recognition receptors act to provide a comprehensive surveillance network that has the potential to induce interferon expression in response to any viral infection. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 03/2015; 479-480. DOI:10.1016/j.virol.2015.02.051 · 3.32 Impact Factor
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