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The complement system plays a central role in immunity and inflammation, although certain pathogens can exploit complement to undermine protective immunity. In this context, the periodontal keystone pathogen Porphyromonas gingivalis was previously shown by our group to evade killing by neutrophils or macrophages through exploitation of complement C5a receptor 1 (C5aR1) and complement receptor 3 (CR3). Here, we examined whether P. gingivalis uses complement receptors to also subvert killing by dendritic cells. In line with earlier independent studies, intracellular viable P. gingivalis bacteria could be recovered from mouse bone-marrow-derived dendritic cells (BMDC) or human monocyte-derived dendritic cells (MDDC) exposed to the pathogen. However, in the presence of C5a, the intracellular survival of P. gingivalis was significantly decreased in a C5aR1-dependent way. Further work using wild-type and receptor-knockout BMDC showed that, in the presence of C3a, the C3a receptor (C3aR) similarly enhanced the intracellular killing of P. gingivalis. In contrast, C5aR2, an alternative receptor for C5a (G protein-coupled receptor 77), was associated with increased intracellular P. gingivalis viable counts, consistent with the notion that C5aR2 functions as a negative regulator of C5aR1 activity. Moreover, P. gingivalis failed to use CR3 as a phagocytic receptor in BMDC, in contrast to our earlier findings in macrophages where CR3-mediated uptake promotes P. gingivalis survival. Collectively, these data show that complement receptors mediate cell-type-specific effects on how innate leukocytes handle P. gingivalis, which appears to exploit complement to preferentially evade those cells (neutrophils and macrophages) that are most often encountered in its predominant niche, the periodontal pocket. [ABSTRACT FROM AUTHOR]

An editorial is presented on the potential of metabolic nuclear receptors (NRs) to act in a homeostatic rather than an anti-inflammatory mode in their role as integrators of metabolic and immunological signaling. The consideration of NRs as important targets for drug discovery as attributed to their inherent features is explored. The advantages of small-molecule therapeutics including stability in biological fluids, simple supply chain, and oral bioavailability are tackled.

In periodontitis, dysbiotic microbial communities exhibit synergistic interactions for enhanced protection from host defenses, nutrient acquisition, and persistence in an inflammatory environment. This review discusses evidence that periodontitis-associated communities are 'inflammo- philic' (=loving or attracted to inflammation) in that they have evolved to not only endure inflammation but also to take advantage of it. In this regard, inflammation can drive the selection and enrichment of these pathogenic communities by providing a source of nutrients in the form of tissue breakdown products (e.g. degraded collagen peptides and heme-containing compounds). In contrast, those species that cannot benefit from the altered ecological conditions of the inflammatory environment, or for which host inflammation is detrimental, are likely to be outcompeted. Consistent with the concept that inflammation fosters the growth of dysbiotic microbial communities, the bacterial biomass of human periodontitis-associated biofilms was shown to increase with increasing periodontal inflammation. Conversely, anti-inflammatory treatments in animal models of periodontitis were shown to diminish the periodontal bacterial load, in addition to protecting from bone loss. The selective flourishing of inflammophilic bacteria can perpetuate inflammatory tissue destruction by setting off a 'vicious cycle' for disease progression, in which dysbiosis and inflammation reinforce each other. Therefore, the control of inflammation appears to be central to the treatment of periodontitis, as it is likely to control both dysbiosis and disease progression. [ABSTRACT FROM AUTHOR]

In monocytes and macrophages, the interaction of Porphyromonas gingivalis with Toll-like receptor 2 ( TLR2) leads to the activation of a MyD88-dependent antimicrobial pathway and a phosphatidylinositol-3 kinase ( PI3K) -dependent pro-adhesive pathway, which activates the β2-integrin complement receptor 3 ( CR3). By means of its fimbriae, P. gingivalis binds CXC-chemokine receptor 4 ( CXCR4) and induces crosstalk with TLR2 that inhibits the MyD88-dependent antimicrobial pathway. In this paper, we investigated the impact of the P. gingivalis- CXCR4 interaction on the pro-adhesive pathway. Using human monocytes, mouse macrophages, or receptor-transfected cell lines, we showed that the binding of P. gingivalis fimbriae to CXCR4 induces CR3 activation via PI3K, albeit in a TLR2-independent manner. An isogenic strain of P. gingivalis expressing mutant fimbriae that do not interact with CXCR4 failed to efficiently activate CR3, leading to enhanced susceptibility to killing in vivo compared with the wild-type organism. This in vivo observation is consistent with previous findings that activated CR3 mediates safe entry of P. gingivalis into macrophages. Taken together with our previous work, these results indicate that the interaction of P. gingivalis with CXCR4 leads to inhibition of antimicrobial responses and enhancement of pro-adhesive responses, thereby maximizing its adaptive fitness in the mammalian host. [ABSTRACT FROM AUTHOR]

Recent advancements in the periodontal research field are consistent with a new model of pathogenesis according to which periodontitis is initiated by a synergistic and dysbiotic microbial community rather than by select 'periopathogens', such as the 'red complex'. In this polymicrobial synergy, different members or specific gene combinations within the community fulfill distinct roles that converge to shape and stabilize a disease-provoking microbiota. One of the core requirements for a potentially pathogenic community to arise involves the capacity of certain species, termed 'keystone pathogens', to modulate the host response in ways that impair immune surveillance and tip the balance from homeostasis to dysbiosis. Keystone pathogens also elevate the virulence of the entire microbial community through interactive communication with accessory pathogens. Other important core functions for pathogenicity require the expression of diverse molecules (e.g. appropriate adhesins, cognate receptors, proteolytic enzymes and proinflammatory surface structures/ligands), which in combination act as community virulence factors to nutritionally sustain a heterotypic, compatible and proinflammatory microbial community that elicits a non-resolving and tissue-destructive host response. On the basis of the fundamental concepts underlying this model of periodontal pathogenesis, that is, polymicrobial synergy and dysbiosis, we term it the PSD model. [ABSTRACT FROM AUTHOR]

Microbial pathogens have evolved mechanisms to proactively manipulate innate immunity, thereby improving their fitness in mammalian hosts. We have previously shown that Porphyromonas gingivalis exploits CXC-chemokine receptor-4 (CXCR4) to instigate a subversive crosstalk with Toll-like receptor 2 that inhibits leukocyte killing of this periodontal pathogen. However, whether CXCR4 plays a role in periodontal disease pathogenesis has not been previously addressed. Here, we hypothesized that CXCR4 is required for P. gingivalis virulence in the periodontium and that treatment with AMD3100, a potent CXCR4 antagonist, would inhibit P. gingivalis-induced periodontitis. Indeed, mice given AMD3100 via osmotic minipumps became resistant to induction of periodontal bone loss following oral inoculation with P. gingivalis. AMD3100 appeared to act in an antimicrobial manner, because mice treated with AMD3100 were protected against P. gingivalis colonization and the associated elevation of the total microbiota counts in the periodontal tissue. Moreover, even when administered 2 weeks after infection, AMD3100 halted the progression of P. gingivalis-induced periodontal bone loss. Therefore, AMD3100 can act in both preventive and therapeutic ways and CXCR4 antagonism could be a promising novel approach to treat human periodontitis. [ABSTRACT FROM AUTHOR]

Summary Elderly individuals display increased susceptibility to chronic inflammatory diseases and microbial infections, such as periodontitis and oral aspiration pneumonia. The resurgent interest in innate immunity in the 2000s has been accompanied by parallel studies to understand the impact of aging on the function of the innate immune system, which not only provides first-line defense but is essential for the development of adaptive immunity. This review summarizes and discusses our current understanding of age-associated molecular alterations in neutrophils and macrophages, key inflammatory phagocytes implicated in both protective and destructive host responses. The analysis of recent literature suggests that, in advanced age, phagocytes undergo significant changes in signal transduction pathways that may affect their ability to perform antimicrobial functions or regulate the inflammatory response. These abnormalities are expected to contribute to the pathology of oral infection-driven inflammatory diseases in the elderly. Moreover, the elucidation of age-associated defects in the innate immune system will facilitate the development of intervention therapeutic strategies to promote or restore innate immune function and improve the quality of health in old age. [ABSTRACT FROM AUTHOR]

The evidence of a specific bacterial cause of dental caries and of the function of the salivary glands as an effector site of the mucosal immune system has provided a scientific basis for the development of a vaccine against this highly prevalent and costly oral disease. Research efforts towards developing an effective and safe caries vaccine have been facilitated by progress in molecular biology, with the cloning and functional characterization of virulence factors from mutans streptococci, the principal causative agent of dental caries, and advancements in mucosal immunology, including the development of sophisticated antigen deliv-ery systems and adjuvants that stimulate the induction of salivary immunoglob-ulin A antibody responses. Cell-surface fibrillar proteins, which mediate adher-ence to the salivary pellicle, and glucosyltransferase enzymes, which synthesize adhesive glucans and allow microbial accumulation, are virulence components of mutans streptococci, and primary candidates for a human caries vaccine. Infants, representing the primary target population for a caries vaccine, become mucosally immunocompetent and secrete salivary immunoglobulin A antibodies during the first weeks after birth, whereas mutans streptococci colonize the tooth surfaces at a discrete time period that extends around 26 months of life. Therefore, immunization when infants are about one year old may establish effective immunity against an ensuing colonization attempts by mutans streptococci. The present review criti- cally evaluates recent progress in this field of dental research and attempts to stress the protective potential as well as limitations of caries immunization. [ABSTRACT FROM AUTHOR]

There is increasing appreciation that complement dysregulation lies at the heart of numerous immune-mediated and inflammatory disorders. Complement inhibitors are therefore being evaluated as new therapeutic options in various clinical translation programs and the first clinically approved complement-targeted drugs have profoundly impacted the management of certain complement-mediated diseases. Among the many members of the intricate protein network of complement, the central component C3 represents a 'hot-spot' for complement-targeted therapeutic intervention. C3 modulates both innate and adaptive immune responses and is linked to diverse immunomodulatory systems and biological processes that affect human pathophysiology. Compelling evidence from preclinical disease models has shown that C3 interception may offer multiple benefits over existing therapies or even reveal novel therapeutic avenues in disorders that are not commonly regarded as complement-driven, such as periodontal disease. Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Introduction: The fimA-encoded fimbriae of the periodontal pathogen Porphyromonas gingivalis display genetic diversity. Type I fimbriated P. gingivalis (Pg-I) has been most widely studied at the molecular level, whereas Pg-II is the most frequent isolate from severe periodontitis. Methods: To investigate virulence differences between Types I and II fimbriae, we examined strains 33277 (Pg-I) and OMZ314 (Pg-II), reciprocal swap mutants (i.e. expressing the heterologous fimbrial type), and their respective FimA-deficient derivatives. These organisms were tested in a mouse periodontitis model and in interactions with mouse macrophages, a cell type that plays important roles in chronic infections. Results: Strain 33277 induced significantly more periodontal bone loss than OMZ314 and substitution of Type II fimbriae with Type I in OMZ314 resulted in a more virulent strain than the parent organism. However, the presence of Type II fimbriae was associated with increased proinflammatory and invasive activities in macrophages. Conclusion: The inverse relationship between proinflammatory potential and ability to cause experimental periodontitis may suggest that an aggressive phenotype could provoke a host response that would compromise the persistence of the pathogen. [ABSTRACT FROM AUTHOR]