Barton GM, Kagan JCA cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9:535-542

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720-3200, USA.
Nature Reviews Immunology (Impact Factor: 34.99). 07/2009; 9(8):535-42. DOI: 10.1038/nri2587
Source: PubMed


An emerging paradigm in innate immune signalling is that cell biological context can influence the outcome of a ligand-receptor interaction. In this Review we discuss how Toll-like receptor (TLR) activation and signal transduction are regulated by subcellular compartmentalization of receptors and downstream signalling components. In particular, we focus on the functional specialization of TLRs in the endosomal system. We discuss recent studies that illustrate how basic aspects of the cellular machinery contribute to TLR function and regulation. This emerging area of research will provide important information on how immune signal transduction networks depend on (and in some cases influence) the generic regulators that organize eukaryotic cells.

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    • "TLRs can be subdivided into two groups according to their cellular location and type of ligand recognized. TLRs 1, 2, 4, 5, and 6 are usually expressed on the plasma membrane and interact with extracellular ligands from bacteria, parasites, and fungi (Barton and Kagan 2009). TLRs 3, 7, 8, and 9 are mainly expressed intracellularly within endosomes and/or lysosomes and detect nucleic acids with a microbial origin: TLR3 detects double-stranded RNA, TLR7, and TLR8 sense single-stranded RNA, and TLR9 recognizes bacterial single and double-stranded DNA and unmethylated CpG motifs (Arpaia and Barton 2011). "
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    ABSTRACT: Our knowledge of the lagomorph immune system remains largely based upon studies of the European rabbit (Oryctolagus cuniculus), a major model for studies of immunology. Two important and devastating viral diseases, rabbit hemorrhagic disease and myxomatosis, are affecting European rabbit populations. In this context, we discuss the genetic diversity of the European rabbit immune system and extend to available information about other lagomorphs. Regarding innate immunity, we review the most recent advances in identifying interleukins, chemokines and chemokine receptors, Toll-like receptors, antiviral proteins (RIG-I and Trim5), and the genes encoding fucosyltransferases that are utilized by rabbit hemorrhagic disease virus as a portal for invading host respiratory and gut epithelial cells. Evolutionary studies showed that several genes of innate immunity are evolving by strong natural selection. Studies of the leporid CCR5 gene revealed a very dramatic change unique in mammals at the second extracellular loop of CCR5 resulting from a gene conversion event with the paralogous CCR2. For the adaptive immune system, we review genetic diversity at the loci encoding antibody variable and constant regions, the major histocompatibility complex (RLA) and T cells. Studies of IGHV and IGKC genes expressed in leporids are two of the few examples of trans-species polymorphism observed outside of the major histocompatibility complex. In addition, we review some endogenous viruses of lagomorph genomes, the importance of the European rabbit as a model for human disease studies, and the anticipated role of next-generation sequencing in extending knowledge of lagomorph immune systems and their evolution.
    Immunogenetics 09/2015; DOI:10.1007/s00251-015-0868-8 · 2.23 Impact Factor
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    • "Identifying the triggering events of inflammatory responses is one of the major challenges in understanding the connection between inflammation and cancer. Infection is the best characterized triggering factor of inflammation and TLRs are among the well-characterized receptors that initiate infection-mediated inflammatory responses [57]. Here we unrevealed some new aspects of functional consequences of TLR2 and 4 activation in LNCaP, DU145, and PC3 cells, which display low, moderate, and high metastatic potential, respectively [58]. "
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    ABSTRACT: Background Many types of tumors are organized in a hierarchy of heterogeneous cell populations with different molecular signature. Such heterogeneity may be associated with different responsiveness to microenvironment stimuli. In the present study, the effects of lipopolysaccharide (LPS) and lipoteichoic acid (LTA), as well-known mediators of inflammation, on cancerous behavior of three prostate tumor cells, LNCaP, PC3 and DU145, were investigated. Methods Expression of TLR1-10, CD14 and MyD88 transcripts was investigated by RT-PCR. Protein expression of TLR2 and 4 was scrutinized by flow cytometry, immunofluorescent staining and Western blotting. Experiments were set up to assess the effects of LPS and LTA at different concentrations and times on cell proliferation, extracellular matrix invasion, adhesion and cytokine production. Results We showed that prostate cancer cell lines differentially express TLR1-10, MyD88 and CD14 transcripts. DU145 failed to express TLR4 gene. Positively-identified TLR2 protein in all prostate cancer cells and TLR4 protein in PC3 and LNCaP by Western blotting was not accompanied by cell surface expression, as judged by flow cytometry. Immunofluorescent staining clearly demonstrated predominantly perinuclear localization of TLR2 and TLR4. LTA activation of all prostate cancer cells significantly increased cell proliferation. Regardless of lacking TLR4, DU145 cells proliferated in response to LPS treatment. While LPS caused increased invasiveness of LNCaP, invasive capacity of PC3 was significantly reduced after LPS or LTA stimulation. Stimulation of all prostate tumor cells with LTA was associated with increased cell adhesion and IL-8 production. IL-6 production, however, was differentially regulated by LPS stimulation in prostate tumor cells. Conclusion The data shows that cancer cells originated from the same histologically origin exhibit heterogeneous response to the same TLR ligand. Therefore, a thorough and comprehensive judgment on how and to what extent a particular cancer is affected by TLR agonist could not be inferred by studying an individual cell line.
    Cancer Cell International 06/2014; 14(1):54. DOI:10.1186/1475-2867-14-54 · 2.77 Impact Factor
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    • "It has been reported that TLRs localize to different subcellular membranes (Fig. 2). TLR1, TLR2, TLR4, TLR5, and TLR6 localize to the cell surface, whereas TLR3, TLR7, TLR8, and TLR9 are found mainly in cytoplasmic endosomes (30,62). Activated TLR4 at the plasma membrane is internalized into cytoplasm by a clathrin- and dynamin-mediated endocytosis. "
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    ABSTRACT: Lipid components in biological membranes are essential for maintaining cellular function. Phosphoinositides, the phosphorylated derivatives of phosphatidylinositol (PI), regulate many critical cell processes involving membrane signaling, trafficking, and reorganization. Multiple metabolic pathways including phosphoinositide kinases and phosphatases and phospholipases tightly control spatio-temporal concentration of membrane phosphoinositides. Metabolizing enzymes responsible for PI 4,5-bisphosphate (PI(4,5)P2) production or degradation play a regulatory role in Toll-like receptor (TLR) signaling and trafficking. These enzymes include PI 4-phosphate 5-kinase, phosphatase and tensin homolog, PI 3-kinase, and phospholipase C. PI(4,5)P2 mediates the interaction with target cytosolic proteins to induce their membrane translocation, regulate vesicular trafficking, and serve as a precursor for other signaling lipids. TLR activation is important for the innate immune response and is implicated in diverse pathophysiological disorders. TLR signaling is controlled by specific interactions with distinct signaling and sorting adaptors. Importantly, TLR signaling machinery is differentially formed depending on a specific membrane compartment during signaling cascades. Although detailed mechanisms remain to be fully clarified, phosphoinositide metabolism is promising for a better understanding of such spatio-temporal regulation of TLR signaling and trafficking.
    BMB reports 04/2014; 47(7). DOI:10.5483/BMBRep.2014.47.7.088 · 2.60 Impact Factor
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