Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

Abstract

Neutrophil elastase (NE) functions as a host defense factor; however, excessive NE activity can potentially destroy human tissues. Although NE activity is positively correlated to gingival crevicular fluid and clinical attachment loss in periodontitis, the underlying mechanisms by which NE aggravates periodontitis remain elusive. In this study, we investigated how NE induces periodontitis severity and whether NE inhibitors were efficacious in periodontitis treatment. In a ligature-induced murine model of periodontitis, neutrophil recruitment, NE activity, and periodontal bone loss were increased in the periodontal tissue. Local administration of an NE inhibitor significantly decreased NE activity in periodontal tissue and attenuated periodontal bone loss. Furthermore, the transcription of proinflammatory cytokines in the gingiva, which was significantly upregulated in the model of periodontitis, was significantly downregulated by NE inhibitor injection. An in vitro study demonstrated that NE cleaved cell adhesion molecules, such as desmoglein 1, occludin, and E-cadherin, and induced exfoliation of the epithelial keratinous layer in three-dimensional human oral epithelial tissue models. The permeability of fluorescein-5-isothiocyanate-dextran or periodontal pathogen was significantly increased by NE treatment in the human gingival epithelial monolayer. These findings suggest that NE induces the disruption of the gingival epithelial barrier and bacterial invasion in periodontal tissues, aggravating periodontitis.

Salivary E‐cadherin as a biomarker for diagnosis and predicting grade of periodontitis

“…Loss of epithelial barrier is a hallmark of periodontitis which indicates disintegration of cellular attachment including adherens junctions, tight junctions, and desmosomes between these cells 30–32 . Structurally, adherens junctions connect adjacent cells together by interlocking of extracellular E‐cadherin extending from these cells 33 .…”

“…struction and bone resorption are not expressed sufficiently at the early stage of periodontitis which is predominantly characterized by loss of junctional epithelium attachment. Compromised epithelial integrity and downregulation of epithelial proteins could represent attractive surrogates as they are initially affected by the inflammatory signaling in response to a dysbiotic biofilm.Loss of epithelial barrier is a hallmark of periodontitis which indicates disintegration of cellular attachment including adherens junctions, tight junctions, and desmosomes between these cells [30][31][32]. Structurally, adherens junctions connect adjacent cells together by interlocking of extracellular E-cadherin extending from F I G U R E 1 Concentration of salivary E-cadherin in periodontal health (Control) and periodontitis.…”

Choline and geranic acid (CAGE) ionic liquids inhibit both elastase activity and growth of oral bacteria

“…21 Using a ligature-induced murine model of periodontitis, Hiyoshi et al showed that inducing periodontitis led to increased neutrophil elastase activity in the affected tissue and that administering an elastase inhibitor reduced both periodontal bone loss and transcription of proinflammatory factors. 21 This recent finding confirms previous research that found that inhibiting collagenolytic enzymes in general, including but not limited to neutrophil elastase, improves periodontitis outcomes. [22][23][24][25] In summary, these findings suggest that inhibition of neutrophil elastase is a valid approach for the treatment of periodontitis.…”

“…This destabilizing property of ionic liquids was recently investigated by Mota et al as a means to inhibit the inflammatory enzyme elastase for possible application in the treatment of wounds with delayed healing and/or chronic wounds 20 . Elastase can prevent healing by degrading extracellular matrix within the wound site, and has been recently identified as playing an important role in the pathogenesis of periodontitis by disrupting the gingival epithelial barrier and inducing invasion of bacteria in periodontal tissues 21 . Using a ligature‐induced murine model of periodontitis, Hiyoshi et al showed that inducing periodontitis led to increased neutrophil elastase activity in the affected tissue and that administering an elastase inhibitor reduced both periodontal bone loss and transcription of proinflammatory factors 21 .…”

“…Elastase can prevent healing by degrading extracellular matrix within the wound site, and has been recently identified as playing an important role in the pathogenesis of periodontitis by disrupting the gingival epithelial barrier and inducing invasion of bacteria in periodontal tissues 21 . Using a ligature‐induced murine model of periodontitis, Hiyoshi et al showed that inducing periodontitis led to increased neutrophil elastase activity in the affected tissue and that administering an elastase inhibitor reduced both periodontal bone loss and transcription of proinflammatory factors 21 . This recent finding confirms previous research that found that inhibiting collagenolytic enzymes in general, including but not limited to neutrophil elastase, improves periodontitis outcomes 22–25 .…”