Interleukin-17 (also known as interleukin-17A) is a key cytokine that links T-cell activation to neutrophil mobilization and activation. As such, interleukin-17 can mediate protective innate immunity to pathogens or contribute to the pathogenesis of inflammatory diseases, such as psoriasis and rheumatoid arthritis. This review summarizes the basic biology of interleukin-17 and discusses its emerging role in periodontal disease. The current burden of evidence from human and animal model studies suggests that the net effect of interleukin-17 signaling promotes disease development. In addition to promoting neutrophilic inflammation, interleukin-17 has potent pro-osteoclastogenic effects that are likely to contribute to the pathogenesis of periodontitis, rheumatoid arthritis and other diseases involving bone immunopathology. Systemic treatments with anti-interleukin-17 biologics have shown promising results in clinical trials for psoriasis and rheumatoid arthritis; however, their impact on the highly prevalent periodontal disease has not been investigated or reported. Future clinical trials, preferably using locally administered interleukin-17 blockers, are required to implicate conclusivelyinterleukin-17 in periodontitis and, more importantly, to establish an effective adjunctive treatment for this oral inflammatory disease.

/pdf/basic-biology-and-role-of-interleukin-17-in-immunity-and-377l4j4jik.pdf

Basic biology and role of interleukin‐17 in immunity and inflammation

The composition of the subgingival bacterial microbiota is a critical determinant in the health status of periodontal tissues. Gram-negative anaerobes such as Porphyromonas gingivalis are well-established periodontal pathogens, and high numbers of these bacteria are found in the subgingival sulcus of patients with chronic periodontitis (43). However, a burgeoning pool of evidence indicates that these organisms have a far more complex relationship with the host than merely as pathogens. Gram-negative anaerobes are frequently present in the oral cavity of periodontally healthy individuals (23, 44, 92, 121, 127, 128, 170), and indeed health is the most common status of the human gingiva despite years of exposure to a large microbial burden. Periodontal organisms thus appear to have co-evolved with their host to maintain an ecologically balanced association whereby minimal harm is inflicted on, or by, either party. Disease will only ensue when this interaction becomes unbalanced, an event that has been termed an ecological catastrophe (83). Organisms such as P. gingivalis may thus be more accurately characterized as accidental, or host-adapted, pathogens.

In the subgingival compartment, epithelial cells represent a major host interface for colonizing organisms; hence, the interaction between gingival epithelial cells and periodontal bacteria will contribute to the success or failure of colonization, and to the maintenance of health or disease in the host. Undeniably, in the case of P. gingivalis, an intricate and multithreaded relationship exists between the organism and gingival epithelial cells, which, under optimal conditions, results in stable cohabitation, with both bacteria and host cells responding and adapting to the presence of their partner to maintain a state of health. In the event that this relationship becomes perturbed, for example because of an increase in bacterial burden or an inappropriate immune response, the periodontal disease process can be initiated (13).

The ability to adapt in response to the host environment is reflected in the genetic diversity found within many species of periodontal bacteria. Bacteria are masters of adaptation, and at the genetic level are able to rapidly modify and share DNA. For example, there are significant levels of genetic variation among P. gingivalis strains, and many studies have linked this genetic variability to virulence potential (7, 14, 18, 38, 67, 85, 108). Genetic variability among strains is common in bacteria with long-term carrier states, possibly arising from the co-evolutionary dynamic of host–pathogen interactions (62, 123). Genetic variation can produce lineages of bacteria with `good or evil' personalities, in that some are more virulent and associated with disease, whereas other strains of the same species behave in a more commensal manner. In this review, we will discuss the current understanding of pathogenic and commensal aspects of bacterial interactions with periodontal tissues, with a specific focus on P. gingivalis intracellular invasion and molecular modulation of host cells.

/pdf/bacterial-invasion-of-epithelial-cells-and-spreading-in-4ec2dwtf5t.pdf

Bacterial invasion of epithelial cells and spreading in periodontal tissue.

Emerging data on the consequences of the interactions between invasive oral bacteria and host cells have provided new insights into the pathogenesis of periodontal disease. Indeed, modulation of the mucosal epithelial barrier by pathogenic bacteria appears to be a critical step in the initiation and progression of periodontal disease. Periodontopathogens such as Porphyromonas gingivalis have developed different strategies to perturb the structural and functional integrity of the gingival epithelium. P. gingivalis adheres to, invades, and replicates within human epithelial cells. Adhesion of P. gingivalis to host cells is multimodal and involves the interaction of bacterial cell-surface adhesins with receptors expressed on the surfaces of epithelial cells. Internalization of P. gingivalis within host cells is rapid and requires both bacterial contact-dependent components and host-induced signaling pathways. P. gingivalis also subverts host responses to bacterial challenges by inactivating immune cells and molecules and by activating host processes leading to tissue destruction. The adaptive ability of these pathogens that allows them to survive within host cells and degrade periodontal tissue constituents may contribute to the initiation and progression of periodontitis. In this paper, we review current knowledge on the molecular cross-talk between P. gingivalis and gingival epithelial cells in the development of periodontitis.

Porphyromonas gingivalis-epithelial cell interactions in periodontitis

Background and Objective:  Chronic periodontitis, the chronic inflammatory disease of the periodontium, is caused by bacteria and is characterized by an influx of neutrophils into the gingival crevice. Recently, a ‘new’ extracellular neutrophil defense mechanism – neutrophil extracellular traps – has been described. However, their role in periodontitis has not yet been investigated.



Material and Methods:  Clinical examinations, transmission and scanning electron microscopy, as well as cytology and confocal laser-scanning microscopy, were employed to analyze gingiva biopsies and crevicular exudate from patients with chronic periodontitis.



Results:  An abundance of neutrophil extracellular traps and some phagocytic neutrophils was found on the gingival pocket surface and in the purulent crevicular exudate. Finding neutrophil extracellular traps in the spontaneously effused purulent crevicular exudate clearly indicated that they are flushed from the pocket by the crevicular exudate. In cases of dispersal of subgingival plaque bacteria, their trapping by neutrophil extracellular traps in purulent crevicular exudate and on the gingival surface was demonstrated.



Conclusion:  Trapping the crevicular bacteria prevents their adhesion to and invasion of the gingiva. The combination of neutrophil extracellular traps and crevicular exudate outflow appears to be a ‘novel’ defense mechanism for the clearance of crevicular bacteria in chronic periodontitis.

Extracellular neutrophil traps in periodontitis

The presence of Porphyromonas gingivalis in the periodontal pocket and the high levels of gingipain activity detected in gingival crevicular fluid could implicate a role for gingipains in the destruction of the highly vascular periodontal tissue. To explore the effects of these proteases on endothelial cells, we exposed bovine coronary artery endothelial cells and human microvascular endothelial cells to gingipain-active extracellular protein preparations and/or purified gingipains from P. gingivalis. Treated cells exhibited a rapid loss of cell adhesion properties that was followed by apoptotic cell death. Cleavage of N- and VE-cadherin and integrin β1 was observed in immunoblots of cell lysates. There was a direct correlation between the kinetics of cleavage of N- and VE-cadherin and loss of cell adhesion properties. Loss of cell adhesion, as well as N- and VE-cadherin and integrin β1 cleavage, could be inhibited or significantly delayed by preincubation of P. gingivalis W83 gingipain-active extracellular extracts with the cysteine protease inhibitor Nα-p-tosyl-l-lysine chloromethylketone. Furthermore, purified gingipains also induced endothelial cell detachment and apoptosis. Apoptosis-associated events, including annexin V positivity, caspase-3 activation, and cleavage of the caspase substrates poly(ADP-ribose) polymerase and topoisomerase I (Topo I), were observed in endothelial cells after detachment. All of the effects observed were correlated with the different levels of cysteine-dependent proteolytic activity of the extracts tested. Taken together, these results indicate that gingipains from P. gingivalis can alter cell adhesion molecules and induce endothelial cell death, which could have implications for the pathogenicity of this organism.

https://iai.asm.org/content/iai/73/3/1543.full.pdf

Gingipains from Porphyromonas gingivalis W83 Induce Cell Adhesion Molecule Cleavage and Apoptosis in Endothelial Cells

Aim: To assess the potential of gingival crevicular fluid (GCF) from adult periodontitis patients and Porphyromonas gingivalis proteases to activate matrix metalloproteinase 2 (MMP-2) in vitro.

Material and Methods: GCF samples were collected from each of 15 adult periodontitis patients, from a clinically healthy site, a deep (>6 mm) bleeding site, and a deep nonbleeding site. The GCF samples were examined for general proteolytic activity, gelatinolytic activity and ability to activate pro-MMP-2 by zymography. Ultrasonic extracts of a range of clinical isolates of P. gingivalis cells and purified arg- and lys-gingipains were also assessed for their ability to activate pro-MMP-2.

Results: GCF from deep nonbleeding sites showed higher general proteolytic activity than samples from deep bleeding and healthy sites but this did not reach statistical significance. Pefabloc, a general serine protease inhibitor, inhibited the majority (92%) of the proteolytic activity. GCF samples contained neutrophil MMP-9 in its latent form in 93% of the samples, and in its activated form in 40% of the samples. In contrast, MMP-2 was present in only trace amounts in 9% of the samples. When latent MMP-2 was added to these GCF samples, it was converted to the activated form (59 kDa) in 68% of the samples. Lower molecular weight (55 and 45 kDa) activated forms also appeared in 53% of the samples, particularly those from deep sites. Activation to the 55 and 45 kDa forms was inhibited by MSAAPket (a neutrophil elastase inhibitor), whereas Pefabloc completely inhibited the activation of latent MMP-2. All ultrasonic extracts of P. gingivalis activated latent MMP-2 in a concentration- and time-dependent manner. Also, latent MMP-2 was activated by purified arg-gingipain but less efficiently by lys-gingipain.

Conclusion: These findings suggest that P. gingivalis arg-gingipain and neutrophil elastase present in GCF can activate latent MMP-2, which may contribute in vivo to local periodontal tissue destruction.

Activation of human matrix metalloproteinase 2 by gingival crevicular fluid and Porphyromonas gingivalis.

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Activation of human matrix metalloproteinase 2 by gingival crevicular fluid and Porphyromonas gingivalis.