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Periodontitis is one of the most prevalent human inflammatory diseases. It is characterized by periodontal tissue destruction, progressively driven by the host response. In this regard, cytokines associated with tissue destruction, such as interleukin (IL)–6 and IL-23, use a common signaling pathway mediated by STAT3. This transcription factor is also needed for IL-17A production, a key mediator in periodontitis pathogenesis. Although several studies have reported increased activation of STAT3 in experimental periodontitis, a detailed characterization of STAT3 activation in human gingival tissues and its involvement in alveolar bone loss has yet to be explored. Using a cross-sectional study design, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health, particularly in epithelial cells and T cells. Other cell types of hematopoietic and nonhematopoietic origin also display STAT3 activation in gingival tissues. We detected increased STAT3 phosphorylation and expression of STAT3-related genes during experimental periodontitis. Next, we evaluated the role of STAT3 in alveolar bone destruction using a mouse model of STAT3 loss of function (mut- Stat3 mice). Compared with controls, mut- Stat3 mice had reduced alveolar bone loss following ligature-induced periodontitis. We also evaluated pharmacologic inhibition of STAT3 in ligature-induced periodontitis. Like mut- Stat3 mice, mice treated with STAT3 small-molecule inhibitor had reduced bone loss compared with controls. Our results demonstrate that STAT3 activation is increased in epithelial and T cells during periodontitis and indicate a pathogenic role of STAT3 in inflammatory alveolar bone loss. [ABSTRACT FROM AUTHOR]

Neutrophils are abundant, short-lived myeloid cells that are readily recruitable to sites of inflammation, where they serve as first-line defense against infection and other types of insult to the host. In recent years, there has been increased understanding on the involvement of neutrophils in chronic inflammatory diseases, where they may act as direct effectors of destructive inflammation. However, destructive tissue inflammation is also instigated in settings of neutrophil paucity, suggesting that neutrophils also mediate critical homeostatic functions. The activity of neutrophils is regulated by a variety of local tissue factors. In addition, systemic metabolic conditions, such as hypercholesterolemia and hyperglycemia, affect the production and mobilization of neutrophils from the bone marrow. Moreover, according to the recently emerged concept of innate immune memory, the functions of neutrophils can be enhanced through the process of trained granulopoiesis. This process may have both beneficial and potentially destructive effects, depending on context, that is, protective against infections and tumors, while destructive in the context of chronic inflammatory conditions. Although we are far from a complete understanding of the mechanisms underlying the regulation and function of neutrophils, current insights enable the development of targeted therapeutic interventions that can restrain neutrophil-mediated inflammation in chronic inflammatory diseases, such as periodontitis. [ABSTRACT FROM AUTHOR]

Periodontitis is a complex inflammatory disease affecting the supporting structures of teeth and is associated with systemic inflammatory disorders. Regulator of G-protein signaling 12 (RGS12), the largest protein in the RGS protein family, plays a crucial role in the development of inflammation and bone remodeling. However, the role and mechanism(s) by which RGS12 may regulate periodontitis have not been elucidated. Here, we showed that ablation of RGS12 in Mx1+ hematopoietic cells blocked bone loss in the ligature-induced periodontitis model, as evidenced morphometrically and by micro–computed tomography analysis of the alveolar bone. Moreover, hematopoietic cell-specific deletion of RGS12 inhibited osteoclast formation and activity as well as the production of inflammatory cytokines such as IL1β, IL6, and TNFα in the diseased periodontal tissue. In the in vitro experiments, we found that the overexpression of RGS12 promoted the reprogramming of macrophages to the proinflammatory M1 type, but not the anti-inflammatory M2 type, and enhanced the ability of macrophages for migration. Conversely, knockdown of RGS12 in macrophages inhibited the production of inflammatory cytokines and migration of macrophages in response to lipopolysaccharide stimulation. Our results demonstrate for the first time that inhibition of RGS12 in macrophages is a promising therapeutic target for the treatment of periodontitis. [ABSTRACT FROM AUTHOR]

The balance between pro- and anti-inflammatory signals maintains tissue homeostasis and defines the outcome of chronic inflammatory diseases such as periodontitis, a condition that afflicts the tooth-supporting tissues and exerts an impact on systemic health. The induction of tissue inflammation relies heavily on Toll-like receptor (TLR) signaling, which drives a proinflammatory pathway through recruiting myeloid differentiation primary response gene 88 (MyD88) and activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). TLR-induced production of proinflammatory cytokines and chemokines is reined in by anti-inflammatory cytokines, including the transforming growth factor β (TGFβ) family of cytokines. Although Smad6 is a key mediator of TGFβ-induced anti-inflammatory signaling, the exact mechanism by which TGFβ regulates TLR proinflammatory signaling in the periodontal tissue has not been addressed to date. In this study, we demonstrate for the first time that the ability of TGFβ to inhibit TLR-NFκB signaling is mediated by protein arginine methyltransferase 1 (PRMT1)-induced Smad6 methylation. Upon methylation, Smad6 recruited MyD88 and promoted MyD88 degradation, thereby inhibiting NFκB activation. Most important, Smad6 is expressed and methylated in the gingival epithelium, and PRMT1-Smad6 signaling promotes tissue homeostasis by limiting inflammation. Consistent with this, disturbance of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. The dissected mechanism is therapeutically important, as it highlights the manipulation of PRMT1-Smad6 signaling as a novel promising strategy to modulate the host immune response in periodontitis. [ABSTRACT FROM AUTHOR]

The Wingless/integrase-1 (Wnt) family of protein ligands and their functional antagonists, secreted frizzled-related proteins (sFRPs), regulate various biological processes ranging from embryonic development to immunity and inflammation. Wnt5a and sFRP5 comprise a typical ligand/antagonist pair, and the former molecule was recently detected at the messenger RNA (mRNA) level in human periodontitis. The main objective of this study was to investigate the interrelationship of expression of Wnt5a and sFRP5 in human periodontitis (as compared to health) and to determine their roles in inflammation and bone loss in an animal model. We detected both Wnt5a and sFRP5 mRNA in human gingiva, with Wnt5a dominating in diseased and sFRP5 in healthy tissue. Wnt5a and sFRP5 protein colocalized in the gingival epithelium, suggesting epithelial cell expression, which was confirmed in cultured human gingival epithelial cells (HGECs). The HGEC expression of Wnt5a and sFRP5 was differentially regulated by a proinflammatory stimulus (lipopolysaccharide [LPS] from Porphyromonas gingivalis) in a manner consistent with the clinical observations (i.e., LPS upregulated Wnt5a and downregulated sFRP5). In HGECs, exogenously added Wnt5a enhanced whereas sFRP5 inhibited LPS-induced inflammation, as monitored by interleukin 8 production. Consistent with this, local treatment with sFRP5 in mice subjected to ligature-induced periodontitis inhibited inflammation and bone loss, correlating with decreased numbers of osteoclasts in bone tissue sections. As in humans, mouse periodontitis was associated with high expression of Wnt5a and low expression of sFRP5, although this profile was reversed after treatment with sFRP5. In conclusion, we demonstrated a novel reciprocal relationship between sFRP5 and Wnt5a expression in periodontal health and disease, paving the way to clinical investigation of the possibility of using the Wnt5a/sFRP5 ratio as a periodontitis biomarker. Moreover, we showed that sFRP5 blocks experimental periodontal inflammation and bone loss, suggesting a promising platform for the development of a new host modulation therapy in periodontitis. [ABSTRACT FROM AUTHOR]

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]

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]

In recent years, the study of genetic defects arising from inborn errors in immunity has resulted in the discovery of new genes involved in the function of the immune system and in the elucidation of the roles of known genes whose importance was previously unappreciated. With the recent explosion in the field of genomics and the increasing number of genetic defects identified, the study of naturally occurring mutations has become a powerful tool for gaining mechanistic insight into the functions of the human immune system. In this concise perspective, we discuss emerging evidence that inborn errors in immunity constitute real-life models that are indispensable both for the in-depth understanding of human biology and for obtaining critical insights into common diseases, such as those affecting oral health. In the field of oral mucosal immunity, through the study of patients with select gene disruptions, the interleukin-17 (IL-17) pathway has emerged as a critical element in oral immune surveillance and susceptibility to inflammatory disease, with disruptions in the IL-17 axis now strongly linked to mucosal fungal susceptibility, whereas overactivation of the same pathways is linked to inflammatory periodontitis. [ABSTRACT FROM PUBLISHER]

New insights into the biological mechanisms involved in modulating periodontal inflammation and alveolar bone loss are paving the way for novel therapeutic strategies for periodontitis. The neutrophil adhesion cascade for transmigration in response to infection or inflammation is a key paradigm in immunity. Developmental endothelial locus-1 (Del-1) is one of several newly identified endogenous inhibitors of the leukocyte adhesion cascade. Del-1 competes with intercellular adhesion molecule-1 (ICAM-1) on endothelial cells for binding to the LFA-1 integrin on neutrophils, thereby regulating neutrophil recruitment and local inflammation. In animal periodontitis models, Del-1 deficiency resulted in severe inflammation and alveolar bone loss, but local treatment with recombinant Del-1 prevented neutrophil infiltration and bone loss. The expression of Del-1 is inhibited by the pro-inflammatory cytokine IL-17. Nucleic-acidreceptor-mediated inflammatory responses may be important in periodontal disease pathogenesis. Bacterial nucleic acids released during inflammation are detected by host microbial DNA sensors, e.g., Toll-like receptor-9 (TLR-9), leading to the activation of pro- and/or anti-inflammatory signaling pathways. DNA from periodontitis-associated bacteria induced proinflammatory cytokine production in human macrophage-like cells through the TLR-9 and NF-KB signaling pathways, but had less effect on human osteoblasts. Inhibition of TLR-9 signaling in human macrophages reduced cytokine production in response to P. gingivalis DNA. Differential expression of a polymorphic site in the TLR-9 gene promoter region and increased TLR-9 gene and protein expression were reported in chronic periodontitis. Further research to confirm that periodontal bacterial DNA contributes to destructive inflammation in vivo could provide alternative therapeutic targets to control periodontitis. [ABSTRACT FROM AUTHOR]

This review summarizes the current state of knowledge on neutrophil basic biology and discusses how the breakdown of neutrophil homeostasis affects periodontal health. The homeostasis of neutrophils is tightly regulated through coordinated bone marrow production, release into the circulation, transmigration to and activation in peripheral tissues, and clearance of senescent neutrophils. Dysregulation of any of these homeostatic mechanisms at any age can cause severe periodontitis in humans and animal models. Accordingly, both impaired and excessive neutrophil activity (in terms of numbers or immune function) can precipitate periodontitis. Neutrophil defects of congenital origin (e.g., congenital neutropenia, leukocyte adhesion deficiency, and Chediak-Higashi syndrome) are associated with cutaneous and systemic infections and early-onset forms of periodontitis affecting both the primary and permanent dentitions of children. However, the strong association between congenital neutrophil disorders and early-onset periodontitis is not currently adequately explained mechanistically. This suggests the operation of as-yet-unknown molecular mechanisms, although the available body of evidence leaves no doubt that neutrophils are integral to periodontal tissue homeostasis and health. [ABSTRACT FROM PUBLISHER]

An extensive analysis of dental plaque samples over the years has led to the identification of “red” complex oral bacteria that have a strong association with each other and with disease. Consequently, these bacteria have been labeled ‘periopathogens’. Studies with one of these bacteria, Porphyromonas gingivalis, have revealed that it contains several different mechanisms which either impede or modulate periodontal protective mechanisms. In a mouse model of periodontitis, it has been shown that modulation of complement function by P. gingivalis facilitates a significant change in both the amount and composition of the normal oral microbiotia. This altered oral commensal microbiota is responsible for pathologic bone loss in the mouse. Thus, P. gingivalis creates a dysbiosis between the host and dental plaque, and this may represent one mechanism by which periodontitis can be initiated. We have therefore termed P. gingivalis a keystone pathogen. [ABSTRACT FROM PUBLISHER]

Unlabelled: Toll-like receptors play a critical role in innate immunity by detecting invading pathogens. The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response. The present review will cover the fundamental signaling pathways utilized by TLRs and how these pathways regulate the innate immune response to pathogens.Abbreviations: TLR, Toll-like receptor; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; APC, antigen-presenting cell; IL, interleukin; TIR, Toll/IL-1R homology; MyD88, myeloid differentiation factor 88; IFN, interferon; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRAK, IL-1R-associated kinase; TAK1, TGF-β-activated kinase; TAB1, TAK1-binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MAPK, mitogen-activated protein kinase; NLR, NOD-like receptors; LRR, leucine-rich repeats; DC, dendritic cell; PI3K, phosphoinositide 3-kinases; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; DAF, decay-accelerating factor; IKK, IκB kinase; IRF, interferon regulatory factors; TBK1, TANK-binding kinase 1; CARD, caspase activation and recruitment domain; PYD, pyrin N-terminal homology domain; ATF, activating transcription factor; and PTEN, phosphatase and tensin homolog. [ABSTRACT FROM AUTHOR]

For almost two decades, the Th1/Th2 paradigm has offered a productive conceptual framework for investigating the pathogenesis of periodontitis. However, as with many other inflammatory diseases, the observed role of T-cell-mediated immunity in periodontitis did not readily fit this model. A new subset of CD4+ T-cells was recently discovered that explains many of the discrepancies in the classic Th1/Th2 model, and has been termed "Th17" based on its secretion of the novel proinflammatory cytokine IL-17. The identification of Th17 cells as a novel effector T-cell population compels re-examination of periodontitis in the context of the new subset and its signature cytokines. This review aims to offer a clarifying insight into periodontal pathogenesis under the extended Th1/Th2/Th17 paradigm, and is predicated on the principle that periodontal disease activity is determined by a complex interplay between the immune system and periodontal pathogens. The re-examination of existing periodontal literature and further studies in the light of these new discoveries may help explain how the inflammatory response results in damage to the periodontium while generally failing to control the pathogens. This knowledge is essential for the development of immunomodulatory intervention strategies for fine-tuning the host response to maximize the protective and minimize the destructive aspects of the periodontal host response. Moreover, with the advent of anti-cytokine biologic drugs that target the Th1 and Th17 pathways in autoimmunity, the potential consequences to periodontal disease susceptibility in humans need to be understood. Abbreviations: CIA, collagen-induced arthritis; CMI, cell-mediated immunity; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; ERK, extracellular signal-regulated kinase; IL-, interleukin; IRF, interferon regulatory factor; KO, knockout; PGE2, prostaglandin E2; PRR, pattern-recognition receptor; ROR, retinoic acid receptor; TCR, T-cell receptor; Th, T helper; TLR, Toll-like receptor; TRIF, TIR-domain-containing adapter protein-inducing interferon-beta. [ABSTRACT FROM AUTHOR]

The heat-labile enterotoxins, such as cholera toxin (CT), and the labile toxins types I and II (LT-I and LT-II) of Escherichia coli have been extensively studied for their immunomodulatory properties, which result in the enhancement of immune responses. Despite superficial similarity in structure, in which a toxic A subunit is coupled to a pentameric binding B subunit, different toxins have different immunological properties. Administration of appropriate antigens admixed with or coupled to these toxins by oral, intranasal, or other routes in experimental animals induces mucosal IgA and circulating IgG antibodies that have protective potential against a variety of enteric, respiratory, or genital infections. These include the generation of salivary antibodies that may protect against colonization with mutans streptococci and the development of dental caries. However, exploitation of these adjuvants for human use requires an understanding of their mode of action and the separation of their desirable immunomodulatory properties from their toxicity. Recent findings have revealed that adjuvant action is not critically dependent upon the enzymic activity of the A subunits, and that the isolated B subunits may exert different effects on cells of the immune system than do the intact toxins. Interaction of the toxins with immunocompetent cells is not exclusively dependent upon their conventional ganglioside receptors. Immunomodulatory effects have been observed on dendritic cells, macrophages, CD4+ and CD8+ Tcells, and B-cells. Numerous factors—including the precise form of the toxin adjuvant, properties of the antigen, whether and how they are coupled, route of administration, and species of animal model—affect the outcome, whether this is enhanced humoral and cellular immunity, or specific induced tolerance toward the antigen. [ABSTRACT FROM AUTHOR]

Adherence to salivary pellicle-coated tooth surfaces and aggregation by salivary components of Streptococcus mutans involves a major cell surface protein termed antigen (Ag) I/II. The objectives of this study were to evaluate the affinity and specificity of the interactions between AgI/II and human saliva in assays of 125I-AgI/II binding to saliva-coated hydroxyapatite (SHA) and of S. mutans aggregation by salivary agglutinin (SAG), monitored turbidimetrically. 125I-AgI/II binding to SHA followed saturation kinetics, and Scatchard plot analysis indicated two binding sites with dissociation constants of the order of 10-10 mol/L and 10-9 mol/L. The binding to SHA of the C-terminal one-third of AgI/II which corresponds to AgIl was less than one-fifth that of the whole molecule and did not show evidence of saturation. The binding of 125I-AgI/II was inhibited by native or recombinant fragments that mapped in the N-terminal part of the molecule and that contained the alanine-rich repeat region, whereas fragments mapping at the central or C-terminal one-third had no effect. As with binding to SHA, the regions of AgI/II which inhibited aggregation mapped at the N-terminal part of the molecule, but, in addition, a recombinant segment mapping at the central part and containing the proline-rich repeat region was also inhibitory. The S. mutans-aggregating activity of SAG or whole saliva was inhibited by amino compounds, and most strongly by L-lysine and analogues possessing ω-primary amine groups. These data support the role of AgI/II as an adhesin with high-affinity binding for SHA receptors, mediated by the N-terminal part of the molecule. This region is also involved in SAG- induced S. mutans aggregation, which is sensitive to amino compounds. [ABSTRACT FROM AUTHOR]