Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Zhang, Yanghui; Gaekwad, Jidnyasa; Wolfert, Margreet A.; Boons, Geert‐Jan

doi:10.1039/b809090d

Cited by 43 publications

(43 citation statements)

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“…Within the limitations of the study, the present findings are consistent with other observations [71]–[73], which demonstrates that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS interact differentially with TLR2 and TLR4, and critically determine the subsequent activation of the downstream signal transduction cascade that differentially modulates immuno-inflammatory response. This reflects the critical importance of lipid A structural heterogeneity of P. gingivalis LPS in activation of TLR receptors and their downstream signal transduction pathways in P. gingivalis -host cell interactions.…”

Section: Discussionsupporting

confidence: 92%

Tetra- and Penta-Acylated Lipid A Structures of Porphyromonas gingivalis LPS Differentially Activate TLR4-Mediated NF-κB Signal Transduction Cascade and Immuno-Inflammatory Response in Human Gingival Fibroblasts

et al. 2013

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Background Porphyromonas gingivalis is a major pathogen of periodontal disease that affects a majority of adults worldwide. Increasing evidence shows that periodontal disease is linked to various systemic diseases like diabetes and cardiovascular disease, by contributing to increased systemic levels of inflammation. Lipopolysaccharides (LPS), as a key virulent attribute of P. gingivalis, possesses significant amount of lipid A heterogeneity containing tetra- (LPS1435/1449) and penta-acylated (LPS1690) structures. Hitherto, the exact molecular mechanism of P. gingivalis LPS involved in periodontal pathogenesis remains unclear, due to limited understanding of the specific receptors and signaling pathways involved in LPS-host cell interactions.Methodology/Principal FindingsThis study systematically investigated the effects of P. gingivalis LPS1435/1449 and LPS1690 on the expression of TLR2 and TLR4 signal transduction and the activation of pro-inflammatory cytokines IL-6 and IL-8 in human gingival fibroblasts (HGFs). We found that LPS1435/1449 and LPS1690 differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS1690 but not by LPS1435/1449. In addition, LPS1690 induced significant expression of NF-κB and p38 MPAK pathways-related genes, such as NFKBIA, NFKB1, IKBKB, MAP2K4 and MAPK8. Notably, the pro-inflammatory genes including GM-CSF, CXCL10, G-CSF, IL-6, IL-8 and CCL2 were significantly upregulated by LPS1690 while down-regulated by LPS1435/1449. Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS1690-induced expression of IL-6 and IL-8 in HGFs.Conclusions/SignificanceThe present study suggests that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS differentially activate TLR4-mediated NF-κB signaling pathway, and significantly modulate the expression of IL-6 and IL-8 in HGFs. The ability to alter the lipid A structure of LPS could be one of the strategies carried-out by P. gingivalis to evade innate host defense in gingival tissues, thereby contributing to periodontal pathogenesis.

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Section: Discussionsupporting

confidence: 92%

Tetra- and Penta-Acylated Lipid A Structures of Porphyromonas gingivalis LPS Differentially Activate TLR4-Mediated NF-κB Signal Transduction Cascade and Immuno-Inflammatory Response in Human Gingival Fibroblasts

et al. 2013

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“…Found to be potent antagonists of human TLR4 (Zhang, et al, 2008e) Tetrasaccharide -fluorescent label from K30 Antigen TOF (CHCA) TOF (DHB) Dansyl label added with click chemistry …”

Section: Tofmentioning

confidence: 99%

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

Harvey

2011

Mass Spectrometry Reviews

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This review is the fifth update of the original review, published in 1999, on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2008. The first section of the review covers fundamental studies, fragmentation of carbohydrate ions, use of derivatives and new software developments for analysis of carbohydrate spectra. Among newer areas of method development are glycan arrays, MALDI imaging and the use of ion mobility spectrometry. The second section of the review discusses applications of MALDI MS to the analysis of different types of carbohydrate. Specific compound classes that are covered include carbohydrate polymers from plants, N- and O-linked glycans from glycoproteins, biopharmaceuticals, glycated proteins, glycolipids, glycosides and various other natural products. There is a short section on the use of MALDI mass spectrometry for the study of enzymes involved in glycan processing and a section on the use of MALDI MS to monitor products of the chemical synthesis of carbohydrates with emphasis on carbohydrate-protein complexes and glycodendrimers. Corresponding analyses by electrospray ionization now appear to outnumber those performed by MALDI and the amount of literature makes a comprehensive review on this technique impractical. However, most of the work relating to sample preparation and glycan synthesis is equally relevant to electrospray and, consequently, those proposing analyses by electrospray should also find material in this review of interest.

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“…This led us to speculate that TLR2 activation by LPS could be triggered by specific P. gingivalis lipid A structures (22). However, an evaluation of a range of synthetic molecules modeled upon distinct P. gingivalis lipid A structures has shown that they act through TLR4 and not TLR2 (28)(29)(30)(31), raising the possibility that TLR2 stimulation by LPS is due to tightly bound copurifying molecules. Adding weight to this hypothesis, and similar to observations made with E. coli LPS preparations (32,33), a lipoprotein with TLR2 agonist activity was identified from P. gingivalis LPS preparations (34).…”

mentioning

confidence: 99%

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

et al. 2013

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Infection by the chronic periodontitis-associated pathogen Porphyromonas gingivalis activates a Toll-like receptor 2 (TLR2) response that triggers inflammation in the host but also promotes bacterial persistence. Our aim was to define ligands on the surfaces of intact P. gingivalis cells that determine its ability to activate TLR2. Molecules previously reported as TLR2 agonists include lipopolysaccharide (LPS), fimbriae, the lipoprotein PG1828, and phosphoceramides. We demonstrate that these molecules do not comprise the major factors responsible for stimulating TLR2 by whole bacterial cells. First, P. gingivalis mutants devoid of the reported protein agonists, PG1828 and fimbriae, activate TLR2 as strongly as the wild type. Second, two-phase extraction of whole bacteria resulted in a preponderance of TLR2 agonist activity partitioning to the hydrophilic phase, demonstrating that phosphoceramides are not a major TLR2 ligand. Third, analysis of LPS revealed that TLR2 activation is independent of lipid A structural variants. Instead, activation of TLR2 and TLR2/TLR1 by LPS is in large part due to copurifying molecules that are sensitive to the action of the enzyme lipoprotein lipase. Strikingly, intact P. gingivalis bacterial cells treated with lipoprotein lipase were attenuated in their ability to activate TLR2. We propose that a novel class of molecules comprised by lipoproteins constitutes the major determinants that confer to P. gingivalis the ability to stimulate TLR2 signaling. Porphyromonas gingivalis is a Gram-negative anaerobic bacterium associated with chronic periodontitis, an inflammatory disease that results in tooth loss (1). P. gingivalis is typically found in diseased subgingival sites (2). Mouse models of P. gingivalis infection have demonstrated its capacity to elicit periodontitis, as measured by bone loss (3-5). A recent study revealed a key role played by P. gingivalis infection in altering the composition, and increasing the abundance, of oral commensal bacteria in conventionally grown mice (4). The interaction between an increasing bacterial load and the host innate immune system triggers a proinflammatory response, which is considered a major factor in causing periodontitis.The Toll-like receptor (TLR) family of innate immune receptors plays a pivotal role in host surveillance and in initiating an immediate immune response that is designed to neutralize microbial threats to the host (6). P. gingivalis infection triggers activation of TLR2, which leads to production of proinflammatory cytokines. One impact of these cytokines is a damaging effect on alveolar bone, resulting in bone loss, as demonstrated by studies using TLR2 Ϫ/Ϫ mice (3, 7). Paradoxically, the robust TLR2 proinflammatory response does not clear P. gingivalis infection in wild-type mice. Instead, the infection is cleared more efficiently in TLR2 Ϫ/Ϫ mice and by macrophages from TLR2 Ϫ/Ϫ mice (3, 5, 7), indicating that TLR2 stimulation confers enhanced persistence to this chronic pathogen. A lack of bacterial clearance illustra...

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Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Cited by 43 publications

References 52 publications

Tetra- and Penta-Acylated Lipid A Structures of Porphyromonas gingivalis LPS Differentially Activate TLR4-Mediated NF-κB Signal Transduction Cascade and Immuno-Inflammatory Response in Human Gingival Fibroblasts

Tetra- and Penta-Acylated Lipid A Structures of Porphyromonas gingivalis LPS Differentially Activate TLR4-Mediated NF-κB Signal Transduction Cascade and Immuno-Inflammatory Response in Human Gingival Fibroblasts

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2007–2008

A Novel Class of Lipoprotein Lipase-Sensitive Molecules Mediates Toll-Like Receptor 2 Activation by Porphyromonas gingivalis

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