Effects of <i>Porphyromonas gingivalis</i> on the Central Nervous System: Activation of Glial Cells and Exacerbation of Experimental Autoimmune Encephalomyelitis

Shapira, Lior; Ayalon, Sharon; Brenner, Talma

doi:10.1902/jop.2002.73.5.511

Cited by 45 publications

(38 citation statements)

References 29 publications

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“…P. gingivalis LPS has been reported to use either TLR4 or TLR2 in its signaling, 19,[23][24][25] and Shapira et al reported that injecting whole killed P. gingivalis bacteria into subcutaneous chambers in SJL mice resulted in enhancement of EAE. 26 In contrast to these studies that used whole bacteria or P. gingivalis LPS, our studies focused on uniquely structured, non-LPS lipids produced by P. gingivalis. We have previously characterized these phosphorylated sphingolipid classes, termed phosphorylated dihydroceramides, produced by this organism and reported that these lipids promote inflammatory responses in human fibroblasts in vitro.…”

Section: Discussionmentioning

confidence: 99%

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Nichols

Housley

O'Conor

et al. 2009

The American Journal of Pathology

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Recent reports suggest that commensal bacteria may play a down-regulatory role in autoimmune disease. In the present studies, we demonstrate that phosphorylated dihydroceramides, uniquely structured lipids derived from the common human oral bacterium Porphyromonas gingivalis and from bacteria commonly found in the gastrointestinal tract and other organs, are capable of enhancing autoimmunity. We have previously reported that these lipids have proinflammatory effects on human fibroblasts in vitro and, in preliminary studies, have recovered these lipids from surgically removed human carotid atheroma, suggesting that they may play a role in human inflammatory disease. To investigate whether these lipids have functional effects on autoimmunity, we administered phosphorylated dihydroceramides to mice with the murine model of multiple sclerosis, experimental allergic encephalomyelitis (EAE). We find that these lipids, and particularly the phosphoethanolamine dihydroceramide (PE DHC) fraction, significantly enhanced EAE. Mechanistically, PE DHC enhances EAE in mice lacking natural killer T cells, fails to enhance EAE in Toll-like receptor 2 (TLR2)-deficient mice and, in vitro, induces dendritic cell interleukin-6 secretion in a TLR2-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Nichols

Housley

O'Conor

et al. 2009

The American Journal of Pathology

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“…For example, heat-killed P. gingivalis administered through a subcutaneous chamber to mice with induced experimental autoimmune encephalomyelitis aggravated the disease compared to controls [109] possibly through an inflammatory mechanism as P. gingivalis -derived LPS stimulated NO and prostaglandin E2 (PGE2) in rat glial cells [108,109]. Since P. gingivalis LPS stimulates the human cells through CD14 and toll-like receptors (TLR-2 and 4), it has been suggested that perhaps brain-induced inflammation induced by P. gingivalis -derived LPS may be mediated by these receptors [50].…”

Section: Association Between Periodontal Disease and Progression Of Amentioning

confidence: 99%

Alzheimer's Disease and Peripheral Infections: The Possible Contribution from Periodontal Infections, Model and Hypothesis

Kamer¹,

Dasanayake²,

Craig³

et al. 2008

JAD

153

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Abstract. Alzheimer's disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

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“…Recent epidemiological studies have demonstrated a strong association between periodontal disease and serious systemic diseases such as atherosclerosis and coronary heart diseases (DeStefano et al, 1993;Beck et al, 1999), diabetes (Teng et al, 2002), pneumonia (Scannapieco, 1999), multiple sclerosis (Shapira et al, 2002), and preterm birth and low birth weight (Romero et al, 2002;Jeffcoat et al, 2003). A marked increase in the prevalence of periodontal disease over the past three decades has thus prompted efforts to characterize its pathogenesis and to develop new approaches to the therapy.…”

mentioning

confidence: 99%

Suppression of Pathogenicity of Porphyromonas gingivalis by Newly Developed Gingipain Inhibitors

Kadowaki¹,

Baba²,

Abe³

et al. 2004

Molecular Pharmacology

114

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Arg-gingipain (Rgp) and Lys-gingipain (Kgp) are cysteine proteinases produced by Porphyromonas gingivalis, a major etiological bacterium of periodontal diseases. Here we show a series of small peptide analogs able to inhibit either Rgp or Kgp, which are synthesized on the basis of the cleavage site specificity of human salivary histatins by each enzyme. Among this series of compounds, carbobenzoxy-Lys-Arg-CO-Lys-N-(CH 3 ) 2 (KYT-1) and carbobenzoxy-Glu(NHN(CH 3 )Ph)-Lys-CO-NHCH 2 Ph (KYT-36) were found to be the most potent inhibitors of Rgp and Kgp, respectively, with K i values of 10 Ϫ11 to 10 Ϫ10 M order. Both inhibitors exhibited slight or no inhibition on mammalian proteinases such as trypsin and cathepsins B, L, and H. All of the virulence induced by the culture supernatant of P. gingivalis tested, including the degradation of various host proteins such as human type I collagen, immunoglobulins, fibronectin, and fibrinogen, disruption of the bactericidal activity of polymorphonuclear leukocytes, and enhancement of the vascular permeability, were strongly inhibited by a combined action of both inhibitors. The functions essential for the bacterium to grow and survive in the periodontal pocket, such as coaggregation and acquisition of amino acids, were also strongly inhibited by the combined action of both inhibitors. The disruption of the adhesion and viability of human fibroblasts and hemagglutination by the organism were strongly suppressed by a single use of KYT-1. These results thus indicate that the newly developed KYT-1 and KYT-36 both should provide a broader application in studies of this important class of enzymes and facilitate the development of new approaches to periodontal diseases.

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Effects of Porphyromonas gingivalis on the Central Nervous System: Activation of Glial Cells and Exacerbation of Experimental Autoimmune Encephalomyelitis

Abstract: The present study provides evidence that infection with a periodontal pathogen, such as P. gingivalis, may play a role in the pathogenesis of CNS inflammatory disorders such as MS.

Cited by 45 publications

References 29 publications

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Unique Lipids from a Common Human Bacterium Represent a New Class of Toll-Like Receptor 2 Ligands Capable of Enhancing Autoimmunity

Alzheimer's Disease and Peripheral Infections: The Possible Contribution from Periodontal Infections, Model and Hypothesis

Suppression of Pathogenicity of Porphyromonas gingivalis by Newly Developed Gingipain Inhibitors

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