Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

Muthukuru, Manoj; Jotwani, Ravi; Cutler, Christopher W.

doi:10.1128/iai.73.2.687-694.2005

Cited by 126 publications

(168 citation statements)

References 40 publications

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“…Whereas some reports indicated a paucity of Th1-inducing IL-12, 56 we noted a significant increase in IL-12p35 and p40 expression and in secreted IL-12p40/p70 protein in response to P. gingivalis LPS. Although we detected P. gingivalis-induced IL-10, as reported, 57 levels of IL-12 were consistently higher. Importantly, increased P. gingivalis-induced expression of heterodimeric IL-23, composed of p40 and p19, and connected to Th17 survival, were consistent with pro-inflammatory IL-17 ϩ cells within the lesions and inflamed gingiva.…”

Section: Discussionmentioning

confidence: 46%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigenpresenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive pathways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation.

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Section: Discussionmentioning

confidence: 46%

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Nares

Moutsopoulos

Angelov

et al. 2009

The American Journal of Pathology

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“…The multifunctional adhesive capacity of P. gingivalis fimbriae may result from versatile structural motifs, which in turn may offer pattern recognition substrate for the innate host defense. Indeed pattern recognition receptors (PRRs) 2 of the innate immune system can detect the presence of fimbriae and respond by inducing release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) (13-15).Monocytes/macrophages constitute a major source of TNF-␣ production, and their number increases in periodontal inflammation compared with healthy periodontal tissue (16,17). These cells express multiple PRRs, including CD14 and CD11b/CD18, which play an important accessory role in Toll-like receptor (TLR)-dependent innate immune and inflammatory responses (18 -20).…”

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confidence: 99%

“…Monocytes/macrophages constitute a major source of TNF-␣ production, and their number increases in periodontal inflammation compared with healthy periodontal tissue (16,17). These cells express multiple PRRs, including CD14 and CD11b/CD18, which play an important accessory role in Toll-like receptor (TLR)-dependent innate immune and inflammatory responses (18 -20).…”

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confidence: 99%

Peptide Mapping of Bacterial Fimbrial Epitopes Interacting with Pattern Recognition Receptors

Hajishengallis

Ratti

Harokopakis

2005

Journal of Biological Chemistry

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The fimbriae of the oral pathogen Porphyromonas gingivalis induce Toll-like receptor 2 (TLR2)-dependent macrophage activation upon their recognition by CD14 and the ␤ 2 integrin CD11b/ CD18. To map functional epitopes of fimbriae that interact with these pattern recognition receptors (PRRs), we examined 20 synthetic peptides covering the entire length of the 41-kDa fimbrillin subunit. Using direct or competitive inhibition assays for receptor binding or cell activation, the CD14 binding activity of fimbriae was localized to residues 69 -90 and was essential for TLR2-dependent cytokine induction. The CD11b/CD18 binding activity of fimbriae was localized to two neighboring epitopes defined by residues 166 -185 and 206 -225. Unlike epitope 69 -90 that constitutively bound CD14, the CD11b/CD18 binding activity of epitopes 166 -185 and 206 -225 was inducible by integrin activators. The CD11b/CD18 binding activity played a contributory role to TLR2-dependent induction of tumor necrosis factor-␣ by fimbriae but was involved in specific down-regulation of interleukin-12. Cell activation by a combination of fimbrillin peptides corresponding to the CD14 and CD11b/CD18 binding activities resulted in higher tumor necrosis factor-␣ responses than would be expected from a simply additive effect, attributable to CD14-dependent inside-out signaling leading to enhanced binding interactions with CD11b/CD18. These data suggest that P. gingivalis fimbriae display a modular structure that interacts through discrete epitopes and in a regulated mode with distinct PRRs, which in turn differentially modulate the state of cell activation. Elucidation of pathogen interactions with PRRs at the molecular level may glean insight into host defense mechanisms as well as into microbial strategies that subvert innate immunity.Porphyromonas gingivalis is a Gram-negative bacterium that has been strongly associated with periodontal disease (1) and has more recently been implicated in systemic inflammatory conditions such as atherosclerosis (2-4). Studies in animal models of periodontitis or atherosclerosis have established the fimbriae (filamentous appendages on the cell surface) of P. gingivalis as a major virulence factor of this pathogen (5, 6). In vitro mechanistic studies have shown that fimbriae display adhesive properties that enable P. gingivalis to bind diverse extracellular substrates (7,8) or to interact with a variety of cell types (9 -12). The multifunctional adhesive capacity of P. gingivalis fimbriae may result from versatile structural motifs, which in turn may offer pattern recognition substrate for the innate host defense. Indeed pattern recognition receptors (PRRs) 2 of the innate immune system can detect the presence of fimbriae and respond by inducing release of proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣) (13-15).Monocytes/macrophages constitute a major source of TNF-␣ production, and their number increases in periodontal inflammation compared with healthy periodontal tissue (16,17). These cells express mu...

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“…Antigen-presenting cells made tolerant ("tolerized") in this manner have a reduced capacity to initiate an adaptive immune response (7,8,29). The molecular mechanisms involved in endotoxin tolerance are still unclear but include downregulation of TLRs (17,20), alterations in signaling events downstream of Toll-like receptor (TLR) signaling (7,16), and the induction of immune regulatory molecules such as Src homology 2 (SH2)-containing inositol phosphatase (SHIP), an inhibitor of NF-B signaling (14,23,24).…”

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confidence: 99%

“…The Institutional Review Board approved this protocol. The clinical criteria for CP and subject gingival health were as previously described (13,17). Briefly, in CP subjects, the sextant from which tissue was harvested exhibited more than four teeth, with probing depths of 5 to 10 mm, attachment loss of 5 to 10 mm, alveolar…”

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confidence: 99%

Upregulation of Immunoregulatory Src Homology 2 Molecule Containing Inositol Phosphatase and Mononuclear Cell Hyporesponsiveness in Oral Mucosa during Chronic Periodontitis

Muthukuru

Cutler

2006

Infect Immun

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Our group and others have shown in vitro that repeated exposure of human mononuclear cells (MNC) to lipopolysaccharide can induce endotoxin tolerance, evidenced by downregulation of TLR2 and TLR4 mRNA and surface protein; moreover, the ability of the MNC to secrete inflammatory cytokines is reduced. In situ studies performed on diseased and healthy gingiva suggest that a similar pattern of endotoxin tolerance occurs in human oral mucosa with chronic periodontitis (CP). We hypothesized that this represents a fundamental immunoregulatory mechanism to restore immune homeostasis and protect the host from further tissue damage. In the current study, we extend these published studies by providing evidence that Src homology 2 containing inositol phosphatase, an inhibitor of NF-B activation and a negative regulator of the immune response, is upregulated in the oral mucosa during CP compared to its level during gingival health. We have also isolated MNC from patients with CP and those with healthy gingiva and show that MNC from CP subjects have a reduced capacity to upregulate TLR2, TLR4, and interleukin-1␤ in response to endotoxin. Thus, we provide more definitive evidence for a basic mechanism of immunoregulation in the oral mucosa.The ability to discriminate harmful microbes from commensal species is probably the most important property of the mucosal immune system, essential for maintaining a healthy host. Mucosal diseases, where the host inappropriately responds to commensal gut flora and to food antigens, are exemplified by Crohn's disease (1) and celiac disease (12), respectively. The Toll-like receptors (TLRs) are pattern recognition receptors that can rapidly identify microbial structures (e.g., peptidoglycan and lipopolysaccharide [LPS]) (2, 26, 30) and provoke an appropriate adaptive immune response (19). Chronic exposure to microbial structures such as LPS can lead to a selective and a transient hyporesponsive state called endotoxin tolerance. Antigen-presenting cells made tolerant ("tolerized") in this manner have a reduced capacity to initiate an adaptive immune response (7,8,29). The molecular mechanisms involved in endotoxin tolerance are still unclear but include downregulation of TLRs (17,20), alterations in signaling events downstream of Toll-like receptor (TLR) signaling (7, 16), and the induction of immune regulatory molecules such as Src homology 2 (SH2)-containing inositol phosphatase (SHIP), an inhibitor of NF-B signaling (14,23,24).Chronic periodontitis (CP) is an inflammatory disease of the oral mucosa (22) mediated by exposure to dental plaque, which contains Ͼ500 taxa of oral bacteria, ϳ60% of which are cultivable (15, 21). Nonetheless, the disease appears to be associated with a small subset of species that share the common property of being gram negative, i.e., producing LPS (4, 9, 25). Our published results suggest that the host may respond to the products of these gram-negative species by downregulation of TLR2 and TLR4 at the level of transcription (17). This observation was corroborated ...

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Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis

Abstract: The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (

Cited by 126 publications

References 40 publications

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

Peptide Mapping of Bacterial Fimbrial Epitopes Interacting with Pattern Recognition Receptors

Upregulation of Immunoregulatory Src Homology 2 Molecule Containing Inositol Phosphatase and Mononuclear Cell Hyporesponsiveness in Oral Mucosa during Chronic Periodontitis

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