Porphyromonas gingivalis is a Gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis and is a member of more than 500 bacterial species that live in the oral cavity. This ...anaerobic bacterium is a natural member of the oral microbiome, yet it can become highly destructive (termed pathobiont) and proliferate to high cell numbers in periodontal lesions: this is attributed to its arsenal of specialized virulence factors. The purpose of this review is to provide an overview of one of the main periodontal pathogens—Porphyromonas gingivalis. This bacterium, along with Treponema denticola and Tannerella forsythia, constitute the “red complex,” a prototype polybacterial pathogenic consortium in periodontitis. This review outlines Porphyromonas gingivalis structure, its metabolism, its ability to colonize the epithelial cells, and its influence upon the host immunity.
To explore the pathogenic association between periodontal disease and rheumatoid arthritis focusing on the role of Porphyromonas gingivalis.
In the last decades our knowledge about the pathogenesis ...of rheumatoid arthritis substantially changed. Several evidences demonstrated that the initial production of autoantibodies is not localized in the joint, rather in other immunological-active sites. A central role seems to be played by periodontal disease, in particular because of the ability of P. gingivalis to induce citrullination, the posttranslational modification leading to the production of anticitrullinated protein/peptide antibodies, the most sensitive and specific rheumatoid arthritis biomarker.
The pathogenic role of P. gingivalis has been demonstrated in mouse models in which arthritis was either triggered or worsened in infected animals. P. gingivalis showed its detrimental role not only by inducing citrullination but also by means of other key mechanisms including induction of NETosis, osteoclastogenesis, and Th17 proinflammatory response leading to bone damage and systemic inflammation.
•Porphyromonas gingivalis (Pg) could induce depression-like behaviors.•Astrocytic p75NTR decreased in Pg-colonized mice.•Overexpression of p75NTR in astrocytes rescued depressive ...behaviors.•Antibiotic therapy ameliorated Pg-induced depressive behavior in mice.
Many cross-sectional epidemiological studies have shown the incidence of periodontitis is positive correlated with that of depression. However, their causal relationship and underlying mechanism are largely unknown. Porphyromonas gingivalis (Pg) is the main pathogen for periodontitis. Employing female mice treated with Pg every other day for 4 weeks, we found that Pg-mice showed obvious depression-like behavior, an increased number of activated astrocytes and decreased levels of mature brain derived neurotrophic factor (BDNF) and astrocytic p75NTR in the hippocampus. Both hippocampal injection of BDNF and overexpression of p75NTR in astrocytes alleviated Pg-induced depression-like behavior in mice. Moreover, Pg-lipopolysaccharides (LPS) generated similar phenotypes, which were reversed by the TLR-4 inhibitor TAK242. Our results suggest that Pg-LPS decreases the level of astrocytic p75NTR and then downregulates BDNF maturation, leading to depression-like behavior in mice. Our study provides the first evidence that Pg is a modifiable risk factor for depression and uncovers a novel therapeutic target for the treatment of depression.
•Human β-defensin 3 (hBD3) reduced periodontal inflammation in mice.•The mechanism might have some relation with inflammation response of macrophages.•hBD3 attenuated the polarization of RAW 264.7 ...cells into M1 phenotype.
Human β-defensin 3 (hBD3) is a cationic peptide with immunomodulatory effects on both innate and acquired immune responses. Periodontitis, an inflammatory disease that extends deep into periodontal tissues, causes the loss of supporting structures around the tooth. The present study assessed the effects of hBD3 as a monotherapy for periodontitis in mice and explored its potential mechanism. In vivo, hBD3 inhibited the levels of tumour necrosis factor (TNF)-α, interleukin-6, and matrix metalloprotease-9 in periodontium exposed to Porphyromonas gingivalis (P.g) in a mouse periodontitis model; reduced osteoclast formation and lower alveolar bone loss were also observed. In addition, hBD3 was related to the expression of polarization signature molecules in circulating monocytes. In vitro, hBD3 notably suppressed the production of TNF-α and interleukin-6 in RAW 264.7 cells stimulated by the lipopolysaccharide of P.g. Moreover, hBD3 attenuated polarization of RAW 264.7 cells into the M1 phenotype, with reduced activation of nuclear factor-κB signal transduction. In conclusion, hBD3 exhibits potent anti-periodontitis properties both in vitro and in vivo, and this effect may be correlated to inhibition of the nuclear factor-κB pathway and macrophage polarization.
The relationship of
and oral squamous cell carcinoma (OSCC) has been studied for several years. Previous studies have focused on the direct effect of
on the activities of primary epithelial cells and ...OSCC cells. However, the immune system is responsible for mediating cancer development, whether
can affect oral cancer immunity has seldom been explored to date. In this study, we investigated the role of
in the immunoevasion of OSCC. We evaluated the effect of
on the phagocytosis of Cal-27 cells (OSCC cell line) by bone marrow-derived macrophages in vitro and studied the effect of
on the growth of OSCC and the polarization of tumor-associated macrophages in vivo. We found that
was able to inhibit the phagocytosis of Cal-27 cells by macrophages, and membrane-component molecules of
, such as proteins, were speculated to be the effector components. In addition, sustained infection with antibiotics-inactivated
promoted OSCC growth in mice and induced the polarization of macrophages into M2 tumor-associated macrophages, which mainly display protumor properties. Transcriptome analysis and quantitative RT-PCR revealed that
infection upregulated the expression of genes encoding protumor molecules in Cal-27 cells (
,
, and
) and in macrophages (
,
, and
). Our in vitro and in vivo data suggest that
can promote immunoevasion of oral cancer by protecting cancer from macrophage attack. To our knowledge, the present study reveals a novel mechanism by which
promotes OSCC development.
Bone destruction in inflammatory osteolytic diseases including periodontitis is related to excessive activity of osteoclasts (OC), which originate from precursor cells of the myeloid lineage, termed ...osteoclast precursors (OCP). In contrast to ample knowledge that we currently have on mature OC, little is known about OCP and their regulation during bacterial infection. Therefore, this study aimed to identify and characterize OCP following chronic infection with a periodontal bacteria Porphyromonas gingivalis (Pg). We used a microosmotic pump to continually release Pg subcutaneously in a murine model. Two weeks after Pg infection, the frequency of CD11b+c‐fms+Ly6Chi population is significantly elevated within the bone marrow, spleen, and peripheral blood. In vitro and in vivo studies identified these cells as the OCP‐containing population and Pg infection significantly enhanced the osteoclastogenic activity of these cells. Furthermore, mRNA sequencing analysis indicated a unique gene and pathway profile in CD11b+c‐fms+Ly6Chi population following Pg infection, with changes in genes and pathways related to OC differentiation, cell proliferation and apoptosis, inflammatory response, phagocytosis, and immunity, as well as antigen processing and presentation. Moreover, using IL‐6 knockout mice, we found that IL‐6 is important for Pg‐induced accumulation of CD11b+c‐fms+Ly6Chi population from the bone marrow and periphery. Our results provide new insight into the characterization and regulation of OCP following a chronic bacterial infection. This knowledge is relevant to the understanding of the pathogenesis of bacteria‐induced bone loss, and to the identification of potential therapeutic targets of bone loss diseases.
Graphical
Chronic Porphyromonas gingivalis infection promotes CD11b+c‐fms+Ly6Chi OCP accumulation in BM and periphery through elevated serum IL‐6 and enhances their osteoclastogenic potential through changed gene signatures
Periodontal disease is a polymicrobial inflammatory disease that leads to chronic systemic inflammation and direct infiltration of bacteria/bacterial components, which may contribute to the ...development of Alzheimer's disease. ApoE-/- mice were orally infected (n = 12) with Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum as mono- and polymicrobial infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic infection. Bacterial genomic DNA was isolated from all brain tissues except for the F. nucleatum mono-infected group. Polymerase chain reaction was performed using universal 16 s rDNA primers and species-specific primer sets for each organism to determine whether the infecting pathogens accessed the brain. Sequencing amplification products confirmed the invasion of bacteria into the brain during infection. The innate immune responses were detected using antibodies against complement activation products of C3 convertase stage and the membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9 out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and control groups demonstrated strong intracellular labeling with C3 and C9, due to on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12 infected mice brains demonstrated characteristic opsonization with C3 activation fragments (p = 0.032). These results show that the oral pathogen P. gingivalis was able to access the ApoE-/- mice brain and thereby contributed to complement activation with bystander neuronal injury.
Abstract Background Chronic inflammation in periodontal disease has been suggested as a potential risk factor in Alzheimer’s disease (AD). The purpose of this study was to examine serum antibody ...levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects. Methods Serum samples from 158 participants in the Biologically Resilient Adults in Neurological Studies research program at the University of Kentucky were analyzed for immunoglobulin G antibody levels to seven oral bacteria associated with periodontitis, including Aggregatibacter actinomycetemcomitans , Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum , Tannerella forsythia, and Prevotella intermedia . All 158 participants were cognitively intact at baseline venous blood draw. In all, 81 of the participants developed either mild cognitive impairment (MCI) or AD or both, and 77 controls remained cognitively intact in the years of follow-up. Antibody levels were compared between controls and subjects with AD at baseline draw and after conversion and controls and subjects with MCI at baseline draw and after conversion using the Wilcoxon rank-sum test. AD and MCI participants were not directly compared. Linear regression models were used to adjust for potential confounding. Results Antibody levels to F nucleatum and P intermedia were significantly increased (α = 0.05) at baseline serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status. Conclusions This study provides initial data that demonstrate elevated antibodies to periodontal disease bacteria in subjects years before cognitive impairment and suggests that periodontal disease could potentially contribute to the risk of AD onset/progression. Additional cohort studies profiling oral clinical presentation with systemic response and AD and prospective studies to evaluate any cause-and-effect association are warranted.
A link between obesity and periodontitis has been suggested because of compromised immune response and chronic inflammation in obese patients. In this study, we evaluated the anti-inflammatory ...properties of Kavain, an extract from
, on
-induced inflammation in adipocytes with special focus on peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) and related pathways. The 3T3-L1 mouse preadipocytes and primary adipocytes harvested from mouse adipose tissue were infected with
and inflammation (TNF-α; adiponectin/adipokines), oxidative stress, and adipogenic marker (FAS, CEBPα, and PPAR-γ) expression were measured. Furthermore, effect of PGC-1α knockdown on Kavain action was evaluated. Results showed that
worsens adipocyte dysfunction through increase of TNF-α, IL-6, and iNOS and decrease of PGC-1α and adiponectin. Interestingly, although Kavain obliterated
-induced proinflammatory effects in wild-type cells, Kavain did not affect PGC-1α-deficient cells, strongly advocating for Kavain effects being mediated by PGC-1α. In vivo adipocytes challenged with i.p. injection of
alone or
and Kavain displayed the same phenotype as in vitro adipocytes. Altogether, our findings established anti-inflammatory and antioxidant effects of Kavain on adipocytes and emphasized protective action against
-induced adipogenesis. The use of compounds such as Kavain offer a portal to potential therapeutic approaches to counter chronic inflammation in obesity-related diseases.
Summary
The microbiota plays a central role in human health and disease by shaping immune development, immune responses and metabolism, and by protecting from invading pathogens. Technical advances ...that allow comprehensive characterization of microbial communities by genetic sequencing have sparked the hunt for disease‐modulating bacteria. Emerging studies in humans have linked the increased abundance of Prevotella species at mucosal sites to localized and systemic disease, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low‐grade systemic inflammation. Intriguingly, Prevotella abundance is reduced within the lung microbiota of patients with asthma and chronic obstructive pulmonary disease. Increased Prevotella abundance is associated with augmented T helper type 17 (Th17) ‐mediated mucosal inflammation, which is in line with the marked capacity of Prevotella in driving Th17 immune responses in vitro. Studies indicate that Prevotella predominantly activate Toll‐like receptor 2, leading to production of Th17‐polarizing cytokines by antigen‐presenting cells, including interleukin‐23 (IL‐23) and IL‐1. Furthermore, Prevotella stimulate epithelial cells to produce IL‐8, IL‐6 and CCL20, which can promote mucosal Th17 immune responses and neutrophil recruitment. Prevotella‐mediated mucosal inflammation leads to systemic dissemination of inflammatory mediators, bacteria and bacterial products, which in turn may affect systemic disease outcomes. Studies in mice support a causal role of Prevotella as colonization experiments promote clinical and inflammatory features of human disease. When compared with strict commensal bacteria, Prevotella exhibit increased inflammatory properties, as demonstrated by augmented release of inflammatory mediators from immune cells and various stromal cells. These findings indicate that some Prevotella strains may be clinically important pathobionts that can participate in human disease by promoting chronic inflammation.
Several recent studies link Prevotella colonization at mucosal sites with chronic inflammatory disorders, including periodontitis, bacterial vaginosis, rheumatoid arthritis, metabolic disorders and low‐grade systemic inflammation. This review focuses on the interaction between Prevotella and the immune system, and how Prevotella may promote disease pathology by exacerbating Th17‐mediated inflammation.
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