Lipoproteins of Actinomyces viscosus induce inflammatory responses through TLR2 in human gingival epithelial cells and macrophages

Shimada, Eri; Kataoka, Hideo; Miyazawa, Yuri; Yamamoto, Masahide; Igarashi, Takeshi

doi:10.1016/j.micinf.2012.04.015

Cited by 26 publications

(18 citation statements)

References 24 publications

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“…The observation that lipoprotein lipase inactivates Gram-negative bacterial lipoproteins comes from work done with PG1828 (34), with lipoproteins in Actinomyces viscosus (55), and, in this study, with the synthetic triacylated lipoprotein PAM3CSK4. Interestingly, the TLR2-activating capacity of fimbriae was shown to be attenuated by lipoprotein lipase as well (56).…”

Section: Discussionmentioning

confidence: 81%

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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Section: Discussionmentioning

confidence: 81%

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

et al. 2013

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“…Periodontitis affects many people worldwide and is the main cause of tooth loss, whereas its pathogenesis is quite complicated. In general, periodontitis is an inflammatory disease, usually initiated by periodontal pathogens residing in the dental plaque, including Porphyromonas gingivalis (P. gingivilas) (Byrne et al, 2009), Aggregatibacter actinomycetemcomitans (A. actionomycetecomitans or Aa) (Fine et al, 2007), Tannerella forsythia (T. forsythia) (Tomita et al, 2013), Fusobacterium nucleatum (F. nucleatum), Treponema denticola (T. denticola) (Shin et al, 2013), and Actinomyces viscosus (A. viscosus) (Shimada et al, 2012). However, other risk factors, such as smoking (Kamma et al, 2004), dental calculus (Susin and Albandar, 2005), occlusal trauma (Nakatsu et al, 2014), mouth breathing (Seo et al, 2013), genetic factors (Laine et al, 2012), hormones (Antonoglou et al, 2015), and stress (Huang et al, 2011), can promote the progression of periodontitis.…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death in periodontitis: recent advances and future perspectives

et al. 2016

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Periodontitis is a highly prevalent infectious disease, characterized by destruction of the periodontium, and is the main cause of tooth loss. Periodontitis is initiated by periodontal pathogens, while other risk factors including smoking, stress, and systemic diseases aggravate its progression. Periodontitis affects many people worldwide, but the molecular mechanisms by which pathogens and risk factors destroy the periodontium are unclear. Programmed cell death (PCD), different from necrosis, is an active cell death mediated by a cascade of gene expression events and can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. Although PCD is involved in many inflammatory diseases, its correlation with periodontitis is unclear. After reviewing the relevant published articles, we found that apoptosis has indeed been reported to play a role in periodontitis. However, the role of autophagy in periodontitis needs further verification. Additionally, implication of necroptosis or pyroptosis in periodontitis remains unknown. Therefore, we recommend future studies, which will unravel the pivotal role of PCD in periodontitis, allowing us to prevent, diagnose, and treat the disease, as well as predict its outcomes.

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“…However, the relationship between TLR2 and specific oral bacteria is poorly understood. Recently, we demonstrated that A. viscosus , an oral gram‐positive bacterium frequently isolated from dental plaque, activates human macrophages and oral epithelial cells and that TLR2 plays a key role in this response (Shimada et al ., ). Based on these observations, we hypothesized that TLR2 also may play a key role in initiating R. dentocariosa ‐triggered inflammatory responses.…”

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confidence: 97%

Rothia dentocariosainduces TNF-alpha production in a TLR2-dependent manner

et al. 2013

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Previous work suggested that Rothia dentocariosa is associated with periodontal inflammatory disease. However, little is known about the pathogenicity of this bacterium. To characterize host response to this bacterium, we measured (via ELISA) the amount of TNF-α in the culture supernatant following the stimulation of THP-1 cells (a human acute monocytic leukemia cell line) with R. dentocariosa cells (ATCC14189 and ATCC14190). Exposure to bacterial cells induced the production of TNF-α in a dose-dependent manner. The bacterial induction of TNF-α in THP-1 cells was mediated by the Toll-like receptor 2 (TLR2), as demonstrated by gene-specific knockdown via siRNA, which successfully suppressed TLR2 expression and significantly inhibited the production of TNF-α in the culture supernatant. To confirm the role of TLR2, we examined TLR2-dependent NF-κB activation by R. dentocariosa cells in a distinct cell line. Specifically, HEK293 cells were transiently cotransfected with the human TLR2 gene and an NF-κB-dependent luciferase-encoding reporter gene. The bacterial cells induced NF-κB activation in the transfected HEK293 cells in a dose-dependent manner. In contrast, bacterial cells failed to induce NF-κB activation in cells transfected with pEF6 control vector. Taken together, these results suggest that R. dentocariosa induces host TNF-α production by a TLR2-dependent mechanism.

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Lipoproteins of Actinomyces viscosus induce inflammatory responses through TLR2 in human gingival epithelial cells and macrophages

Cited by 26 publications

References 24 publications

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

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

Programmed cell death in periodontitis: recent advances and future perspectives

Rothia dentocariosainduces TNF-alpha production in a TLR2-dependent manner

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