Sublingual immunization with recombinant GroEL plus CpG-ODN inhibits Porphyromonas gingivalis-induced inflammation and alveolar bone loss.

It has been reported that GroEL, a heat shock protein (HSP) produced by the representative periodontopathogenic bacterium, Porphyromonas gingivalis, induces inflammation-induced osteoclastogenesis and promotes alveolar bone resorption. In this study, we demonstrated the efficacy of a mucosal vaccine targeting GroEL against bone resorption induced by P. gingivalis. Female BALB/c mice received sublingual CpG oligodeoxynucleotide as an adjuvant with recombinant GroEL (rGroEL) prior to P. gingivalis exposure. Animals were euthanized 30 days after P. gingivalis inoculation. Sublingual immunization (SLI) with rGroEL elicited significant rGroEL-specific serum immunoglobulin (Ig)G and salivary IgA antibody (Ab) responses, and these responses were sustained for approximately 1 year. Interestingly, 10-fold more GroEL-specific IgA Ab-producing cells were detected in the submandibular glands (SMGs) than in the spleen. Antigen (Ag)-specific cells isolated from the spleen and SMGs induced significantly higher levels of IFN-γ expression after Ag restimulation in vitro. Flow cytometry illustrated that the frequency of CD11b+ dendritic cells with enhanced expression of CD80, CD86, CD40, and major histocompatibility complex II molecules was significantly increased in the SMGs. Furthermore, SLI with rGroEL significantly suppressed P. gingivalis-induced alveolar bone resorption and P. gingivalis-stimulated tumor necrosis factor-α, interleukin-6, and HSP60 expression in the gingiva. These findings suggest that SLI with rGroEL and CpG oligodeoxynucleotide is a beneficial strategy for preventing periodontal disease, mainly by presenting Ags in the oral region and inducing antibody production in the mucosal and systemic systems.

Actinomyces capricornis sp. nov., isolated from the oral cavity of a Japanese serow.

A novel Gram-positive, facultatively anaerobic, rod-shaped, nonspore forming, nonmotile organism was isolated from a Japanese serow oral cavity. Designated strain MAS-1T , it is most closely related to Actinomyces bowdenii DSM 15435T , with which it shares 98.07% sequence homology in the 16S ribosomal RNA gene. The primarily detected cellular fatty acids in strain MAS-1T were C16:0 and C18:1 w9c. The predominant respiratory quinone was MK-9 (H4 ). The major polar lipids were phosphatidylcholines, phosphatidylinositols, and glycophospholipids. The genomic DNA GC content of the isolate was 71.3 mol%. The digital DNA-DNA hybridization and average nucleotide identity values between MAS-1T and its related species were 23.5%-39.5% and 82.11%-91.01%, respectively, which were below the threshold (70% and 95%, respectively) for species delineation, indicating that strain MAS-1T represents a novel species. Strain MAS-1T can be differentiated from A. bowdenii by their reactions to naphthol-AS-BI-phosphohydrolase, α-galactosidase, ß-galactosidase, and N-acetyl-ß-glucosaminidase, as well as differing acid production from glycogen. Based on the results of genotypic, phenotypic, and biochemical analyses, herein it is proposed that the identified bacteria can be classified as a novel species, Actinomyces capricornis sp. nov., strain MAS-1T (=JCM 34236T = DSM 111732T ).

Lactic acid bacteria prevent both periodontitis and atherosclerosis exacerbated by periodontitis in spontaneously hyperlipidemic mice.

BACKGROUND AND OBJECTIVE: Recent studies have shown a link between periodontal disease and cardiovascular disease. We have previously reported that oral administration of Porphyromonas gingivalis (Pg) accelerates atherosclerosis in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoeshl ) mice. This study evaluated the potential of lactic acid bacteria (LAB) to change the intestinal flora changes induced by periodontopathic bacteria and to prevent/slow down the development of atherosclerosis. METHODS: Lactobacillus gasseri O3-2 (Lg) was orally intubated in Apoeshl mice for 5 weeks. Three weeks after oral intubation, the mice were orally infected with Pg for 2 weeks. RESULTS: Thirty days after the last infection with Pg, Lg+Pg-treated mice showed a significant reduction in alveolar bone loss compared to the Pg-treated group. The Lg treatment restored the Pg-induced intestinal flora disturbance to normal. Furthermore, a significant decrease in atherosclerotic plaque lesion size and suppressed inflammatory cytokine production in the aorta were detected in the Lg + Pg-treated group. In contrast, blood concentrations of TMAO, histidine, and carnitine were enhanced by the Lg treatment but decreased by Lg + Pg treatment. CONCLUSION: These results suggest that oral Lg treatment is effective in preventing periodontitis and atherosclerosis.

Impaired salivary SIgA antibodies elicit oral dysbiosis and subsequent induction of alveolar bone loss.

OBJECTIVE: Secreted IgA (SIgA) plays a central role in preventing bacterial and viral infections on mucosal surfaces by neutralizing toxins and viruses and inhibiting bacterial attachment to epithelial cells. However, the role of salivary SIgA antibodies (Abs) in regulating oral flora is still unknown. This study aimed to evaluate the association among oral bacteria, their metabolites and periodontitis in IgA-deficient (IgA KO) and wild-type (WT) control mice. METHODS: Microcomputed tomography (micro-CT) analysis was used to assess alveolar bone resorption as a development of periodontitis. The bacterial profiles of saliva were determined using the next-generation sequencing assays. Furthermore, the metabolites in saliva were measured and compared using CE-TOFMS. RESULTS: Salivary microbiota of IgA KO mice revealed a remarkably decreased frequency of Streptococcus, and increased percentages of Aggregatibacer, Actinobacillus, and Prevotella at the genus level when compared with those of WT. Compared to WT control mice of the same age, the level of alveolar bone loss was significantly increased in IgA KO mice, and infiltration of osteoclasts was found on the surface of the alveolar bone. The metabolome profile indicated that the metabolites of IgA KO mice had greater variability in carbon metabolic, urea cycle, and lipid pathways than WT mice. CONCLUSION: These results suggest that salivary SIgA plays an important role in regulating and maintaining normal oral microflora to prevent the development of periodontal disease.

Oral bacteria affect the gut microbiome and intestinal immunity.

Recently, it has been suggested that the oral administration of Porphyromonas gingivalis, a keystone pathogen for periodontal disease, induces dysbiosis of the mouse intestinal microbiota and affects intestinal barrier function. Since oral streptococci are the predominant oral bacterial group, we compared the effect of their oral administration on the intestinal tract compared to that of P. gingivalis. Swallowing oral bacteria caused gut dysbiosis, due to increased Bacteroides and Staphylococcus and decreased Lactobacillus spp. Furthermore, oral bacterial infection caused an increase in lactate and decreases in succinate and n-butyrate contents. In the small intestine, the decrease in Th17 cells was considered to be a result of oral bacterial infection, although the population of Treg cells remained unaffected. In addition, oral bacterial challenge increased the M1/M2 macrophage ratio and decreased the immunoglobulin A (IgA) antibody titer in feces. These results suggest that gut dysbiosis caused by oral bacteria may cause a decrease in Th17 cells and fecal IgA levels and an increase in the M1/M2 macrophage ratio, thereby promoting chronic inflammation.

Oral challenge with Streptococcus sanguinis induces aortic inflammation and accelerates atherosclerosis in spontaneously hyperlipidemic mice.

Atherosclerosis is exacerbated by periodontal pathogens, which induce vascular inflammation after entering the bloodstream. Among oral indigenous bacteria, Streptococcus sanguinis and S. anginosus are related to systemic disorders, such as infective endocarditis and abscess, and are sometimes detected in human atherosclerotic plaques or blood. Thus, these oral streptococci may contribute to the progression of atherosclerosis. To test this hypothesis, apolipoprotein E-deficient spontaneously hyperlipidemic mice were intraorally challenged with S. sanguinis or S. anginosus. Atherosclerotic plaque formation increased significantly in the S. sanguinis-challenged group compared with the carboxymethylcellulose-treated control group. Expression levels of mRNAs of proinflammatory cytokines in the aorta and levels of atherosclerosis-related mediators in blood increased upon S. sanguinis challenge. Adaptor molecule TNF receptor-associated factor 6 was also enhanced in the aorta when mice were challenged with S. sanguinis. Furthermore, challenge with S. anginosus induced systemic inflammation, but inflammation-related mRNA expression levels in the aorta only increased slightly and were accompanied by minimal expansion of the lesion area. By contrast, with the exception of IL-1α, the expression levels of inflammation-related genes did not change in gingival tissues of both bacteria- and sham-challenged groups. These results reveal that S. sanguinis causes aortic inflammation that leads to accelerated progression of atherosclerosis.

Lactobacillus helveticus SBT2171 upregulates the expression of ß-defensin and ameliorates periodontal disease caused by Porphyromonas gingivalis.

Antimicrobial peptides play important roles in the innate immune system of various organisms, and they may also be considered to prevent the organisms from infections. In particular, ß-defensins, mainly produced in epithelial cells, are recognized as one of the major antimicrobial peptides in mammals, including humans. In this study, we showed that Lactobacillus helveticus SBT2171 (LH2171), one of the several species of lactic acid bacteria, upregulates the production of ß-defensins in oral epithelial cells in vitro. Moreover, LH2171 reduced the increase of proinflammatory cytokine expression, induced by Porphyromonas gingivalis stimulation, in gingival epithelial cells. These data suggested that LH2171 suppresses P. gingivalis-induced inflammation by upregulating the expression of ß-defensins in gingival epithelial cells. We subsequently investigated the effects of LH2171 in vivo and revealed that ß-defensin expression was increased in the oral cavities of LH2171-fed mice. Furthermore, LH2171 decreased alveolar bone loss, gingival inflammation, and amounts of P. gingivalis-specific 16S ribosomal RNA in the gingiva of P. gingivalis-inoculated mice. Taken together, our results showed that LH2171 upregulates the expression of ß-defensins in oral cavity, thereby decreasing the number of P. gingivalis consequently ameliorating the experimental periodontal disease.

CCR7-deficient mice exhibit a delayed antigen-specific mucosal IgA antibody response to an oral recombinant Salmonella strain.

The migration of antigen (Ag)-loading dendritic cells (DCs) from Peyer's patches (PPs) to the draining mesenteric lymph nodes (MLNs) via chemokine receptor 7 (CCR7) is thought to be an important step in the initiation of acquired immunity. Our previous study showed that PPs were indispensable for Ag-specific secretory (S)IgA antibody (Ab) responses against oral recombinant Salmonella (rSalmonella). In this study, we attempted to show direct PP DC migration to MLNs by employing photoconvertible protein transgenic mice and investigated the role of the CCR7 signaling pathway in mucosal IgA induction. Our results demonstrated an actual flux of DCs from PPs to MLNs. The frequency of CCR7+ CD11c+ DCs in MLNs of PP-deficient mice was reduced, suggesting that some PP DCs migrated via CCR7. Immunization of CCR7-/- mice elicited significantly lower levels of Ag-specific SIgA Ab responses, which was associated with diminished formation of the germinal center in PPs. However, increased SIgA Ab production and dissemination of rSalmonella were observed at later time points. These results suggest that, although CCR7 was required for SIgA induction at normal velocity, the CCR7-mediated pathway is not essential for the induction of Ag-specific SIgA Ab responses to rSalmonella.

Distinct roles for Peyer's patch B cells for induction of antigen-specific IgA antibody responses in mice administered oral recombinant Salmonella.

Our previous study demonstrated an indispensable role of Peyer's patches (PPs) for the induction of antigen-specific secretory (S)IgA antibody responses after oral immunization with recombinant Salmonella expressing fragment C of tetanus toxin (rSalmonella-Tox C). In this study, we defined the PP lymphoid structures and immune cells required for the induction of mucosal SIgA antibody responses. Adoptive transfer of mononuclear cells (MNCs) from PPs into PP-deficient (PP-null) mice failed to elicit tetanus toxoid (TT)-specific mucosal immunity. However, when the same PP MNCs were transferred into lethally irradiated PP-normal recipient mice, PP MNCs preferentially emigrated to recipient PPs, leading to PP lymphoid structures and TT-specific SIgA antibody responses. Significantly reduced numbers of TT-specific IgA antibody-forming cells were detected in the mesenteric lymph nodes (MLNs) and intestinal lamina propria of mice when surface expression of the sphingosine 1-phosphate receptor on lymphocytes was inhibited by its agonist FTY720. However, FTY720 treatment did not alter dendritic cell migration or Salmonella dissemination into these tissues. When rSalmonella-Tox C-stimulated CD4+ T cells isolated from PPs, MLNs and the spleen were co-cultured with B cells from these tissues, significantly increased levels of TT-specific IgA antibody responses were exclusively induced in cultures containing PP B cells. Furthermore, surface IgA+ PP B cells produced TT-specific IgA antibody responses in vitro. These findings suggest that PP lymphoid structures and surface IgA+ PP B cells are essential elements for the induction of antigen-specific intestinal SIgA antibody responses to oral Salmonella.

C/EBPß and YY1 bind and interact with Smad3 to modulate lipopolysaccharide-induced amelotin gene transcription in mouse gingival epithelial cells.

Junctional epithelium (JE) develops from reduced enamel epithelium during tooth formation and is critical for the maintenance of healthy periodontal tissue through ensuring appropriate immune responses and the rapid turnover of gingival epithelial cells. We have previously shown a relationship between inflammatory cytokines and expression of JE-specific genes, such as amelotin (AMTN), in gingival epithelial cells. Here, we elucidated the effects of Porphyromonas gingivalis-derived lipopolysaccharide (Pg LPS) on Amtn gene transcription and the interaction of transcription factors. To determine the molecular basis of transcriptional regulation of the Amtn gene by Pg LPS, we performed real-time PCR and carried out luciferase assays using a mouse Amtn gene promoter linked to a luciferase reporter gene in mouse gingival epithelial GE1 cells. Gel mobility shift and chromatin immunoprecipitation assays were performed to identify response elements bound to LPS-induced transcription factors. Next, we analyzed protein levels of the LPS-induced transcription factors and the interaction of transcription factors by western blotting and immunoprecipitation. LPS increased Amtn mRNA levels and elevated luciferase activities of constructs containing regions between -116 and -238 of the mouse Amtn gene promoter. CCAAT/enhancer-binding protein (C/EBP) 1-, C/EBP2- and Ying Yang 1 (YY1)-nuclear protein complexes were increased by LPS treatment. Furthermore, we identified LPS-modulated interactions with C/EBPß, YY1 and Smad3. These results demonstrate that Pg LPS regulates Amtn gene transcription via binding of C/EBPß-Smad3 and YY1-Smad3 complexes to C/EBP1, C/EBP2 and YY1 response elements in the mouse Amtn gene promoter.

Porphyromonas gingivalis Induces Apoptosis and Autophagy via ER Stress in Human Umbilical Vein Endothelial Cells.

It has been reported that periodontitis is associated with an increased risk of atherosclerosis. Accumulating evidence suggests that endothelial dysfunction is an early marker for atherosclerosis. To determine how periodontal infections contribute to endothelial dysfunction, we examined the effect of Porphyromonas gingivalis on human umbilical vein endothelial cells (HUVEC). P. gingivalis significantly suppressed the viability of HUVEC, induced DNA fragmentation and annexin V staining, and increased caspase-3, caspase-8, and caspase-9 activities. P. gingivalis also increased the expression of GADD153 and GRP78 and caspase-12 activity. Further, P. gingivalis induced autophagy, as evidenced by increased LC3-II and Beclin-1 levels. The suppression of P. gingivalis-induced autophagy by silencing of LC3 with siRNA significantly increased P. gingivalis-induced apoptosis. ER stress inhibitor, salubrinal, suppressed apoptosis and autophagy by inhibiting P. gingivalis-induced DNA fragmentation and LC3-II expression. These data suggest that P. gingivalis infection induces ER stress-mediated apoptosis followed by autophagic response that protects HUVEC from P. gingivalis-mediated apoptosis, potentially amplifying proatherogenic mechanisms in the perturbed vasculature.

Pseudopropionibacterium rubrum sp. nov., a novel red-pigmented species isolated from human gingival sulcus.

In this study, Strain [corrected] SK-1(T), a novel gram-positive, pleomorphic, rod-shaped, non-spore forming, non-motile organism, designated SK-1T , was isolated from human gingival sulcus and found to produce acetic acid, propionic acid, lactic acid, and succinic acid as end products of glucose fermentation. Strain SK-1T is most closely related to Pseudopropionibacterium (Propionibacterium) propionicum with sequence homologies of the 16S rRNA and RNA polymerase ß subunit (rpoB) genes of 96.6% and 93.1%, respectively. The genomic DNA G + C content of the isolate was 61.8 mol%. On the basis of the sequence data of the 16S rRNA and housekeeping (rpoB) genes, a novel taxon is here proposed, Pseudopropionibacterium rubrum sp. nov. (type strain SK-1T = JCM 31317T = DSM 100122T ). The 16S rRNA and rpoB gene sequences of strain SK-1T have been deposited in the DDBJ under the accession numbers LC002971 and LC102236, respectively.

Localization and expression pattern of amelotin, odontogenic ameloblast-associated protein and follicular dendritic cell-secreted protein in the junctional epithelium of inflamed gingiva.

The purpose of this study is to elucidate the localization of amelotin (AMTN), odontogenic ameloblast-associated protein (ODAM) and follicular dendritic cell-secreted protein (FDC-SP) at the junctional epithelium (JE) in Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans infected mice and inflamed and non-inflamed human gingiva. We performed immunostaining to determine the localization and expression pattern of AMTN, ODAM and FDC-SP. AMTN, ODAM and FDC-SP in A. actinomycetemcomitans infected mice did not change dramatically compared with non-infected mice. AMTN and FDC-SP expressions were observed stronger in P. gingivalis infected mice at early stage. However, at the following stage, the coronal part of the AMTN expression disappeared from the JE, and FDC-SP expression decreased due to severe inflammation by P. gingivalis. ODAM expressed internal and external basal lamina, and the expression increased not only at early stage but also at the following stage in the inflammatory JE induced by P. gingivalis. In the human gingival tissues, AMTN was detected at the surface of the sulcular epithelium and JE in the non-inflamed and inflamed gingiva, and the localization did not change the process of inflammation. ODAM and FDC-SP were more widely detected at the sulcular epithelium and JE in the non-inflamed gingiva. In the inflamed gingiva, localization of ODAM and FDC-SP was spread into the gingival epithelium, compared to AMTN. These studies demonstrated that the expression pattern of AMTN, ODAM and FDC-SP at the JE were changed during inflammation process and these three proteins might play an important role in the resistance to inflammation.

Regulation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated periodontal disease.

OBJECTIVE: Porphyromonas gingivalis is involved in the pathogenesis of chronic inflammatory periodontal disease. Recent studies have suggested that the NLRP3 inflammasome plays an important role in the development of chronic inflammation. We investigated a possible association between the inflammasome in gingival inflammation and bone loss induced by P. gingivalis infection using NLRP3-deficient mice. METHODS: Wild-type and NLRP3-deficient mice were injected orally with P. gingivalis. We assessed alveolar bone loss, expression of pro-interleukin (IL)-1ß, pro-IL-18, receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) in gingival tissue, as well as IL-1ß, IL-18, and IL-6 production and caspase-1 activity in peritoneal macrophages. RESULTS: Porphyromonas gingivalis challenge significantly increased alveolar bone loss; gingival gene expression of pro-IL-1ß, pro-IL-18, and RANKL; production of IL-1ß, IL-18, and IL-6; and caspase-1 activity in peritoneal macrophages of wild-type mice, but did not affect NLRP3-deficient mice. Meanwhile, OPG mRNA expression in gingival tissue and peritoneal IL-6 production were significantly higher in NLRP3-knockout mice. CONCLUSIONS: Porphyromonas gingivalis activated innate immune cells via the NLRP3 inflammasome. These results suggest that the NLRP3 inflammasome, followed by a response from the IL-1 family, is critical in periodontal disease induced by wild-type P. gingivalis challenge via sustained inflammation.

Varying butyric acid amounts induce different stress- and cell death-related signals in nerve growth factor-treated PC12 cells: implications in neuropathic pain absence during periodontal disease progression.

Neuropathic pain is absent from the early stages of periodontal disease possibly due to neurite retraction. Butyric acid (BA) is a periodontopathic metabolite that activates several stress-related signals and, likewise, induce neurite retraction. Neuronal cell death is associated to neurite retraction which would suggest that BA-induced neurite retraction is ascribable to neuronal cell death. However, the underlying mechanism of BA-related cell death signaling remains unknown. In this study, we exposed NGF-treated PC12 cells to varying BA concentrations [0 (control), 0.5, 1.0, 5.0 mM] and determined selected stress-related (H2O2, glutathione reductase, calcium (Ca(2+)), plasma membrane Ca(2+) ATPase (PMCA), and GADD153/CHOPS) and cell death-associated (extrinsic: FasL, TNF-α, TWEAK, and TRAIL; intrinsic: cytochrome C (CytC), NF-kB, CASP8, CASP9, CASP10, and CASP3) signals. Similarly, we confirmed cell death execution by chromatin condensation. Our results showed that low (0.5 mM) and high (1.0 and 5.0 mM) BA levels differ in stress and cell death signaling. Moreover, at periodontal disease-level BA concentration (5 mM), we observed that only FasL amounts were affected and occurred concurrently with chromatin condensation insinuating that cells have fully committed to neurodegeneration. Thus, we believe that both stress and cell death signaling in NGF-treated PC12 cells are affected differently depending on BA concentration. In a periodontal disease scenario, we hypothesize that during the early stages, low BA amounts accumulate resulting to both stress- and cell death-related signals that favor neurite non-proliferation, whereas, during the later stages, high BA amounts accumulate resulting to both stress- and cell death-related signals that favor neurodegeneration. More importantly, we propose that neuropathic pain absence at any stage of periodontal disease progression is ascribable to BA accumulation regardless of amount.

Aggregatibacter actinomycetemcomitans induces Th17 cells in atherosclerotic lesions.

Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in atherosclerosis remains poorly understood. We previously reported that Aggregatibacter actinomycetemcomitans (Aa) bacteremia accelerated atherosclerosis accompanied by inflammation in apolipoprotein E-deficient spontaneously hyperlipidemic (Apoe(shl)) mice. In this study, we investigated whether Aa promotes the Th17 inducing pathway in Aa-challenged Apoe(shl) mice. Mice were intravenously injected with live Aa HK1651 or vehicles. Time-course analysis of splenic IL-17(+)CD4(+) cell frequencies, the proximal aorta lesion area, serum IL-17, IL-6, TGF-ß and IL-1ß levels, the mRNA expression of Th17-related molecules such as IL-1ß, IL-6, IL17RA, STAT3, IL-21, IL-23, TGF-ß and RORγt, Th17-related microRNA levels and the levels of AIM-2, Mincle and NLRP3 were examined. Challenge with Aa time dependently induced tropism of Th17 cells in the spleen and increase in atheromatous lesions in the aortic sinus of Apoe(shl) mice. Serum IL-17, IL-6, TGF-ß and IL-1ß levels were significantly enhanced by Aa. The gene expression of IL-1ß, IL-6, IL-17RA, IL-21, IL-23, TGF-ß, STAT3, RORγt, AIM-2, Mincle and NLRP3 was also time dependently stimulated in the aorta of Aa-challenged mice. Furthermore, Aa challenge significantly increased the expression of miR-146b and miR-155 in the aorta. Based on the results, it seems that Aa stimulates Th17 induction that affects the progression of Aa-accelerated atherosclerosis.

High butyric acid amounts induce oxidative stress, alter calcium homeostasis, and cause neurite retraction in nerve growth factor-treated PC12 cells.

Butyric acid (BA) is a common secondary metabolite by-product produced by oral pathogenic bacteria and is detected in high amounts in the gingival tissue of patients with periodontal disease. Previous works have demonstrated that BA can cause oxidative stress in various cell types; however, this was never explored using neuronal cells. Here, we exposed nerve growth factor (NGF)-treated PC1(2) cells to varying BA concentrations (0.5, 1.0, 5.0 mM). We measured total heme, H(2)O(2), catalase, and calcium levels through biochemical assays and visualized the neurite outgrowth after BA treatment. Similarly, we determined the effects of other common periodontal short-chain fatty acids (SCFAs) on neurite outgrowth for comparison. We found that high (1.0 and 5.0 mM) BA concentrations induced oxidative stress and altered calcium homeostasis, whereas low (0.5 mM) BA concentration had no significant effect. Moreover, compared to other SCFAs, we established that only BA was able to induce neurite retraction.

Activation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated atherosclerosis.

Porphyromonas gingivalis has been shown to accelerate atherosclerotic lesion development in hyperlipidemic animals. Atherosclerosis is a disease characterized by inflammation of the arterial wall. Recent studies have suggested that the NLRP3 inflammasome plays an important role in the development of vascular inflammation and atherosclerosis. Herein, we investigated a possible association between the inflammasome in atherosclerosis and periodontal disease induced by P. gingivalis infection using apolipoprotein E-deficient, spontaneously hyperlipidemic (Apoe(shl)) mice. Oral infection with wild-type (WT) P. gingivalis significantly increased the area of aortic sinus covered with atherosclerotic plaque and alveolar bone loss, compared with KDP136 (gingipain-null mutant) or KDP150 (FimA-deficient mutant) challenge. WT challenge also increased IL-1ß, IL-18 and TNF-α production in peritoneal macrophages, and gingival or aortic gene expression of Nod-like receptor family, pyrin domain containing 3 (NLRP3), pro-IL-1ß, pro-IL-18 and pro-caspase-1. Porphyromonas gingivalis genomic DNA was detected more in the aorta, gingival tissue, liver and spleen of WT-challenged mice than those in KDP136- or KDP150-challenged mice. We conclude that WT P. gingivalis activates innate immune cells through the NLRP3 inflammasome compared with KDP136 or KDP150. The NLRP3 inflammasome may play a critical role in periodontal disease and atherosclerosis induced by P. gingivalis challenge through sustained inflammation.

Periodontal Disease-Induced Atherosclerosis and Oxidative Stress.

Periodontal disease is a highly prevalent disorder affecting up to 80% of the global population. Recent epidemiological studies have shown an association between periodontal disease and cardiovascular disease, as oxidative stress plays an important role in chronic inflammatory diseases such as periodontal disease and cardiovascular disease. In this review, we focus on the mechanisms by which periodontopathic bacteria cause chronic inflammation through the enhancement of oxidative stress and accelerate cardiovascular disease. Furthermore, we comment on the antioxidative activity of catechin in atherosclerosis accelerated by periodontitis.