The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens

Underhill, David; Ozinsky, Adrian; Hajjar, Adeline M.; Stevens, Anne M.; Wilson, Christopher; Bassetti, M.; Aderem, Alan

doi:10.1038/44605

Cited by 1,245 publications

(387 citation statements)

References 27 publications

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“…A Pro residue has been shown to play a critical role in TLR4 and TLR2 signaling in mammalian cells. Mutant molecules in which this Pro residue has been changed to a His are unable to trigger NF-B activation (15,37). Interestingly, whereas most mammalian Toll and IL-1R-related receptors harbor a Pro at this position, only 18W in Drosophila presents this conserved Pro.…”

Section: Discussionmentioning

confidence: 99%

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

Tauszig

Jouanguy²,

Hoffmann³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

350

300

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Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides. Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mammalian homologs. Two of these, Toll-like receptor (TLR)2 and TLR4, recently were shown to play a critical role in innate immunity against bacteria. Here we describe six additional Toll-related genes (Toll-3 to Toll-8) in Drosophila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expressed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is expressed only in larvae and adults. By using chimeric constructs, we have tested the capacity of the signaling Toll͞IL-1R homology domains of these receptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll͞IL-1R homology domain. In contrast, none of these constructs activated antibacterial peptide promoters, suggesting that Toll-related receptors are not involved in the regulation of antibacterial peptide expression. This result was independently confirmed by the demonstration that a dominant-negative version of the kinase Pelle can block induction of drosomycin by the cytokine Spaetzle, but does not affect induction of the antibacterial peptide attacin by lipopolysaccharide.

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Section: Discussionmentioning

confidence: 99%

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

Tauszig

Jouanguy²,

Hoffmann³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

350

300

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“…It has been hypothesized that TLRs can accumulate around phagosomes, where they "sample" the contents of the vacuole (24,25,46). Zymosan particles are generated from yeast and activate cells via TLR2 (see Ref.…”

Section: Resultsmentioning

confidence: 99%

“…Zymosan particles are generated from yeast and activate cells via TLR2 (see Ref. 24 and data not shown). We exposed RAW 264.7 macrophages to zymosan particles, and we found most of the particles with cell contact to be rapidly ingested (within 5 min).…”

Section: Resultsmentioning

confidence: 99%

“…Optimal response toward diacylated lipoproteins, such as the 2-kDa macrophage-activating lipoprotein (MALP-2), re-quires heterodimerization of TLR2 with TLR6, whereas heterodimerization of TLR2/TLR1 enhances responses toward triacylated lipopeptides such as Pam 3 -Cys-Ser-Lys 4 (22,23). Other ligands recognized by TLR2 include zymosan, glycolipids from spirochetes, lipoarabinomannan, porins from Neisseria, and certain nonenterobacterial LPS, among others (3,24,25). Little information is available on expression of the TLR2 protein in mice.…”

mentioning

confidence: 99%

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Lipopolysaccharide and Double-stranded RNA Up-regulate Toll-like Receptor 2 Independently of Myeloid Differentiation Factor 88

Nilsen

Nonstad

Khan

et al. 2004

Journal of Biological Chemistry

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Toll-like receptor 2 (TLR2) is a signaling receptor for a variety of microbial products, including bacterial lipoproteins and peptidoglycan, and is central in initiating immune responses toward Gram-positive bacteria, spirochetes, and mycobacteria. The mechanisms behind regulation of TLR2 protein expression are still not well understood. By using a newly developed monoclonal antibody against mouse TLR2, we detected TLR2 protein expression on macrophages, neutrophils, and dendritic cells. Endogenous macrophage TLR2 localized mostly to the cell membrane, with particular accumulation around phagosomes containing zymosan. Treatment of macrophages with the TLR2 antibody diminished cellular response to lipoproteins and down-regulated membrane TLR2. Marked up-regulation of surface TLR2 was observed on macrophages in response to whole bacteria, lipoproteins, lipopolysaccharide, poly(I-C) (doublestranded RNA), R848, and CpG DNA, and this up-regulation appeared to be a very sensitive marker for the presence of microbial products. Up-regulation of TLR2 in response to stimuli correlated with an increased response to secondary lipoprotein exposure following a low concentration of primary lipoprotein challenge. By comparison, exposure to a larger primary challenge induced a hyporeactive state. Most interestingly, lipopolysaccharide-and double-stranded RNA-induced upregulation of surface TLR2 in macrophages was found to be MyD88-independent, whereas the up-regulation in response to lipoproteins, R848, and CpG DNA was absent in MyD88-deficient cells. We conclude that complex mechanisms regulate expression and signaling via TLR2. Up-regulation of TLR2 in the presence of low, yet clinically relevant amounts of microbial products may be an important mechanism by which the immune system boosts its response to a beginning infection.

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“…The extracellular domains of Toll and TLRs contain leucine-rich repeat motives (26). TLR-4, most likely in connection with the adapter molecule MD-2, is the signal transducing receptor for lipopolysaccharide (LPS) from Gram-negative bacteria (19,(27)(28)(29)(30), whereas TLR-2 mediates cellular activation by bacterial lipoproteins, whole Gram-positive bacteria, and yeast (31)(32)(33)(34)(35)(36)(37)(38)(39). Recently, peptidoglycan has been shown to be recognized by TLR-2 and -6 (40), whereas TLR-9 mediates detection of bacterial DNA (41).…”

mentioning

confidence: 99%

Toll-like Receptor-2 Mediates Treponema Glycolipid and Lipoteichoic Acid-induced NF-κB Translocation

Opitz

Schröder

Spreitzer

et al. 2001

Journal of Biological Chemistry

208

141

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Recently Toll-like receptors (TLRs) have been found to be involved in cellular activation by microbial products, including lipopolysaccharide, lipoproteins, and peptidoglycan. Although for these ligands the specific transmembrane signal transducers TLR-4, TLR-2, or TLR-2 and -6 have now been identified, the molecular basis of recognition of lipoteichoic acids (LTAs) and related glycolipids has not been completely understood. In order to determine the role of TLRs in immune cell activation by these stimuli, experiments involving TLR-2-negative cell lines, TLR-expression plasmids, macrophages from TLR-4-deficient C3H/HeJ-mice, and inhibitory TLR-4/MD-2 antibodies were performed. Glycolipids from Treponema maltophilum and Treponema brennaborense, as well as highly purified LTAs from Staphylococcus aureus and Bacillus subtilis exhibited TLR-2 dependence in nuclear factor B activation and cytokine induction; however, T. brennaborense additionally appeared to signal via TLR-4. Fractionation of the T. brennaborense glycolipids by hydrophobic interaction chromatography and subsequent cell stimulation experiments revealed two peaks of activity, one exhibiting TLR-2-, and a second TLR-4-dependence. Furthermore, we show involvement of the signaling molecules MyD88 and NIK in cell stimulation by LTAs and glycolipids by dominant negative overexpression experiments. In summary, the results presented here indicate that TLR-2 is the main receptor for Treponema glycolipid and LTA-mediated inflammatory response.

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The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens

Cited by 1,245 publications

References 27 publications

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

Toll-related receptors and the control of antimicrobial peptide expression inDrosophila

Lipopolysaccharide and Double-stranded RNA Up-regulate Toll-like Receptor 2 Independently of Myeloid Differentiation Factor 88

Toll-like Receptor-2 Mediates Treponema Glycolipid and Lipoteichoic Acid-induced NF-κB Translocation

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