Porphyromonas gingivalis, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1␤ (IL-1␤), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1␤ is linked to periodontal destruction. IL-1␤ synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by which P. gingivalis infection causes IL-1␤ secretion, we examined the characteristics of P. gingivalis-induced signaling in differentiated THP-1 cells. We found that P. gingivalis induces IL-1␤ secretion and inflammatory cell death via caspase-1 activation. We also found that P. gingivalis-induced IL-1␤ secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X 7 receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedes P. gingivalis-induced IL-1␤ release. Our study provides novel insight into the innate immune response against P. gingivalis infection which could potentially be used for the prevention and therapy of periodontitis.

Our study indicates that CGA and CP extracts prevented depressive behavior and thereby have potential as natural antidepressants.

Background: Aggressive periodontitis is characterized by the early-onset and rapid progression of periodontal destruction and is closely associated with Aggregatibacter actinomycetemcomitans. Autophagy is a conserved process that is critical for removing damaged proteins, organelles, and even intracellular pathogens. Therefore, this study examined whether A. actinomycetemcomitans induces autophagy. In addition, the relationship among autophagy, bacterial internalization, and inflammatory molecules in periodontal aggressive inflammation was analyzed. Methods: The expression of autophagy-related proteins in human gingival tissue and THP-1 cells was assessed by Western blot analysis. The formation of light chain 3 (LC3) puncta was examined by confocal microscopy. The degree of bacterial internalization into the cells was determined by the viable cell count. Phagocytosis and reactive oxygen species (ROS) production were measured using confocal microscopy and flow cytometry. Results: When macrophages were infected with live A. actinomycetemcomitans, the autophagy influx was activated by the increase in LC3-II, autophagy-related gene 5/12, and Beclin-1 expression through the Toll-like receptors and extracellular signalregulated kinase signaling pathways. The inhibition of A. actinomycetemcomitansinduced autophagy suppressed bacterial internalization via phagocytosis into the macrophages and increased interleukin (IL)-1 production. Moreover, treatment with an ROS inhibitor inhibited these enhanced inflammatory responses. Conclusions: A. actinomycetemcomitans-induced autophagy promotes bacterial internalization by phagocytosis, which restricts the excessive inflammatory response by downregulating IL-1 and ROS production in macrophages. Thus, A. actinomycetemcomitans-induced autophagy and its role in regulating the inflammatory response may play an important role in the aggressive periodontal inflammatory process, and be a target for the development of new periodontal therapies. K E Y W O R D S aggressive periodontitis, inflammation and innate immunity, pathogenesis of periodontal disease, reactive oxygen species 1682

Aim The aim of this study was to propose biomarker candidates for periodontitis via untargeted metabolomics analysis. Materials and methods Metabolic profiling was performed using saliva samples from 92 healthy controls (H) and 129 periodontitis patients (P) in the discovery cohort using proton nuclear magnetic resonance spectroscopy. Random forest was applied to identify metabolites that significantly differentiated the control group from the periodontitis group. Candidate metabolites were then validated in an independent validation cohort. Results In the discovery set, the metabolic profiles of the P group were clearly separated from those of the H group. A total of 31 metabolites were identified in saliva, and 7 metabolites were selected as candidate biomarkers. These metabolites were further confirmed in the validation set. Ethanol, taurine, isovalerate, butyrate, and glucose were finally confirmed as biomarkers. Furthermore, the biomarker panel showed more than 0.9 of the area under curve value in both discovery and validation sets, indicating that panels were more effective than individual metabolites for diagnosing periodontitis. Conclusions We identified five metabolite biomarkers that discriminated patients with periodontitis from healthy controls in two independent cohorts. These biomarkers have the potential for periodontal screening, detection of periodontitis, and monitoring of the outcome of periodontal therapy.

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Streptococcus mutans (S. mutans), a major aetiologic agent of dental caries, is involved in systemic diseases, such as bacterial endocarditis, if it enters the bloodstream through temporary bacteraemia. Interleukin (IL)-1β, a proinflammatory cytokine, is related to the host defences against pathogens, and its synthesis, maturation, and secretion are tightly regulated by the activation of the inflammasome, an inflammatory signalling complex. This study examined the signalling mechanism of IL-1β secretion and the inflammasome pathway induced by S. mutans to explain the molecular mechanism through which systemic infection by oral streptococci can occur. After infection of THP-1 cells with S. mutans, the expression of inflammasome components was detected using various methods. S. mutans induced IL-1β secretion via caspase-1 activation, and S. mutans-induced IL-1β secretion required absent in melanoma (AIM2), NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing 4 (NLRC4) inflammasome activation. In particular, the S. mutans-induced NLRP3 inflammasome was mediated by adenosine triphosphate (ATP) release, potassium depletion and lysosomal damage. Our study provides novel insight into the innate immune response against S. mutans infection.

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