Aim Periodontitis is an inflammatory disease that destroys both soft and hard periodontal tissues. However, a complex periodontal cytokine network remains unclear. This systematic review explored multiple cytokine gene polymorphisms in the pathogenesis of periodontitis. Material and Methods A systematic search was performed using the databases from previous publications, which indicated the association between cytokine polymorphisms and periodontitis pathogenesis. Meta-analysis was conducted using fixed or randomized models to calculate the significance of multiple cytokine polymorphisms. A total of 147 articles were analyzed with polymorphisms in 12 interleukins [Th1 (IL-2, IFN-γ, and TNF-α), Th2 (IL-4 and IL-13), Th17 (IL-1α, IL-1β, IL-6, and IL-17), and Treg cytokines (IL-10 and TGF-β)]. Doi plot was used to probe the occurrence of publication bias. Results The polymorphisms of IL-2 and TNF-α of Th1 cytokine family may be associated with the pathogenesis or the prevention of periodontitis risk, while the polymorphism of IFN-γ is not related to periodontitis risk. The polymorphisms for IL-4 and IL-13 of Th2 cytokine family are not found to be associated with the pathogenesis of periodontitis. For the polymorphisms of the members of Th17 cytokine family, different IL-1α polymorphisms may have inverse actions in the pathogenesis of periodontitis. IL-1β is a noteworthy cytokine biomarker in periodontitis development and progression. IL-6 may have a protective function in the inflammatory responses of periodontitis, and IL-17 has a weak relationship the inflammatory responses. The polymorphisms for the members of Treg cell cytokines may have a protective function against periodontitis risk. LFK indexes show the major asymmetry due to publication bias. Conclusion IL-1β is a notable cytokine biomarker in periodontitis risk. Treg cytokines favor an anti-inflammatory and protective environment. Further data are needed to confirm the present conclusion due to publication bias.

https://www.frontiersin.org/articles/10.3389/fimmu.2021.713198/pdf

A Systematic Review and Meta-Analysis on Multiple Cytokine Gene Polymorphisms in the Pathogenesis of Periodontitis

Infectious diseases have caused huge economic loss and food security issues in fish aquaculture. Current management and breeding strategies heavily rely on the knowledge of regulative mechanisms underlying disease resistance. Though the intestinal microbial community was linked with disease infection, there is little knowledge about the roles of intestinal microbes in fish disease resistance. Cynoglossus semilaevis is an economically important and widely cultivated flatfish species in China. However, it suffers from outbreaks of vibriosis, which results in huge mortalities and economic loss.Here, we used C. semilaevis as a research model to investigate the host-microbiome interactions in regulating vibriosis resistance. The resistance to vibriosis was reflected in intestinal microbiome on both taxonomic and functional levels. Such differences also influenced the host gene expressions in the resistant family. Moreover, the intestinal microbiome might control the host immunological homeostasis and inflammation to enhance vibriosis resistance through the microbe-intestine-immunity axis. For example, Phaeobacter regulated its hdhA gene and host cyp27a1 gene up-expressed in bile acid biosynthesis pathways, but regulated its trxA gene and host akt gene down-expressed in proinflammatory cytokines biosynthesis pathways, to reduce inflammation and resist disease infection in the resistant family. Furthermore, the combination of intestinal microbes and host genes as biomarkers could accurately differentiate resistant family from susceptible family.Our study uncovered the regulatory patterns of the microbe-intestine-immunity axis that may contribute to vibriosis resistance in C. semilaevis. These findings could facilitate the disease control and selective breeding of superior germplasm with high disease resistance in fish aquaculture. Video Abstract. 

https://microbiomejournal.biomedcentral.com/counter/pdf/10.1186/s40168-022-01346-4

Intestinal microbiome-mediated resistance against vibriosis for Cynoglossus semilaevis

Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors from Gram-negative bacteria (e.g. lipopolysaccharide [LPS]) induce significant pro-inflammatory cytokine expression. Monoamine oxidase (MAO) inhibitors reduce cytokine expression in a variety of inflammatory models and may therefore have therapeutic potential for a number of inflammatory diseases. We tested the anti-inflammatory therapeutic potential of a recently developed reversible MAO-B inhibitor (RG0216) with reduced transport across the blood–brain barrier. In an epithelial cell culture model, RG0216 significantly decreased LPS-induced interleukin (IL)-6 and IL-1 gene and protein expression and was as effective as equimolar concentrations of deprenyl (an existing irreversible MAO-B inhibitor). Hydrogen peroxide and modulating dopamine receptor signaling had no effect on cytokine expression. We showed that LPS-induced expression of IL-6 and IL-1 was cAMP dependent, that IL-6 and IL-1 expression were induced by direct cAMP activation (forskolin) and that RG0216 and deprenyl effectively reduced cAMP-mediated cytokine expression. Targeted protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) activation regulated IL-6 and IL-1 expression albeit in different ways but both cytokines were effectively decreased with RG0216. RG0216 reduction of LPS-induced cytokine expression occurred by acting downstream of the cAMP-PKA/EPAC signaling cascade. This represents a novel mechanism by which MAO-B selective inhibitors regulate LPS-induced IL-6 and IL-1 expression.

Monoamine Oxidase-B Inhibitor Reduction in Pro-Inflammatory Cytokines Mediated by Inhibition of cAMP-PKA/EPAC Signaling

A relevant alternative to enamel matrix derivatives from animal origin could be the use of synthetic amelogenin-derived peptides. This study aimed to assess the effect of a synthetic amelogenin-derived peptide (ADP-5), alone or included in an experimental gellan–xanthan hydrogel, on periodontal cell behavior (gingival fibroblasts, periodontal ligament cells, osteoblasts and cementoblasts). The effect of ADP-5 (50, 100, and 200 µg/mL) on cell metabolic activity was examined using Alamar blue assay, and cell morphology was assessed by confocal imaging. An experimental gellan–xanthan hydrogel was then designed as carrier for ADP-5 and compared to the commercial gel Emdogain®. Alizarin Red was used to determine the periodontal ligament and cementoblasts cell mineralization. The inflammatory profile of these two cells was also quantified using ELISA (vascular endothelial growth factor A, tumor necrosis factor α, and interleukin 11) mediators. ADP-5 enhanced cell proliferation and remineralization; the 100 µg/mL concentration was more efficient than 50 and 200 µg/mL. The ADP-5 experimental hydrogel exhibited equivalent good biological behavior compared to Emdogain® in terms of cell colonization, mineralization, and inflammatory profile. These findings revealed relevant insights regarding the ADP-5 biological behavior. From a clinical perspective, these outcomes could instigate the development of novel functionalized scaffold for periodontal regeneration.

/pdf/amelogenin-derived-peptide-adp-5-hydrogel-for-periodontal-fmbygamu.pdf

Amelogenin-Derived Peptide (ADP-5) Hydrogel for Periodontal Regeneration: An In Vitro Study on Periodontal Cells Cytocompatibility, Remineralization and Inflammatory Profile

OBJECTIVE
Single-cell transcriptomics was used to determine the possible cell-type specificity of periodontitis susceptibility genes.


BACKGROUND
The last decade has witnessed remarkable advances in the field of human genomics. Despite many advances, the genetic factors associated with or contributing to the periodontitis pathogenesis have only been identified to a limited extent and are often poorly validated. Confirming whether a given single nucleotide polymorphism has an association with periodontitis requires a robust mechanistic explanation on the functional consequences of a given genetic variant.


METHODS
We globally assessed the expression of 26 disease-associated genes identified by GWAS within the gingival mucosa. A total of 12 411 cells from 4 different donors were analysed. Differentially expressed genes were analysed using Seurat, a non-parametric Wilcoxon rank sum test. The minimum threshold for significance was defined as p < .05.


RESULTS
This exploration at a cellular-level suggests diverse populations contributing to disease pathogenesis, with macrophages expressing a higher number of the analysed disease-associated genes. IL1B, PTGS2, FCGR2A, IL10 and IL1A specifically showed a more restricted expression in the myeloid lineages.


CONCLUSION
This short report combines human genetics and single-cell genomics to better understand periodontitis by mapping variants to predict their cells of action and putative functions. These findings seem to suggest that innate cell dysfunction is linked to disease susceptibility.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jre.13057

Expression of periodontitis susceptibility genes in human gingiva using single-cell RNA sequencing.

BACKGROUND Periodontitis is an immune-inflammatory disease that leads to the progressive destruction of bone and connective tissue in the periodontal area. The cytokine network plays a primary role in tissue homeostasis, the recruitment of immune cells to control the pathogenic impact and the regulation of osteoclastic function, thus modulating the intensity and duration of the immune response. This review provides an update on the main cytokines implicated in the pathogenesis and progression of periodontitis and their targeting potential in order to enrich current treatment options. METHODS A structured search of bibliographic databases (PubMed, MEDLINE, Scopus) was performed for peer-reviewed cytokine studies focused on periodontitis the last ten years. A qualitative content analysis was performed in screened papers and a critical discussion of main findings is provided. RESULTS An altered cytokine profile has been detected in periodontitis patients and the interplay of pro-inflammatory and/or anti-inflammatory cytokines has been associated with disease pathogenesis. Among the most prominent pro-inflammatory cytokines, TNF-α, IL-1β, IL-17, IL-6 and the chemokines CXCL-6, CXCL-8 are overexpressed in periodontitis patients and correlate with disease progression. On the other hand, the anti-inflammatory IL-4 and IL- 11 levels are reduced while IL-12 and IFN-γ expression play a dual role in periodontal disease. Current periodontitis treatment strategies include selective antibiotics, antimicrobial photodynamic therapy and probiotics, which can modulate the cytokine network and when applied in combination with specific anti-cytokine agents can exert additional beneficial effects. CONCLUSION It is evident that cytokines play a central regulatory role in the inflammatory process and immune cell response that underlies bone destruction in periodontitis. Specific cytokine targeting should be considered as a complementary therapeutic scheme to current periodontal management.

Central Regulatory Role of Cytokines in Periodontitis and Targeting Options.

BACKGROUND
Transient Receptor Potential (TRP) channels are non-selective Ca2+ permeable channels with a wide and dynamic involvement in the perception of environmental stimuli in the oral cavity and a pivotal role in oral tissues' pathology and oral diseases. Several factors secreted during pulpitis and periodontitis, such as pro-inflammatory cytokines, prostaglandins, glutamate, extracellular ATP, and bradykinin, can trigger TRPs, either directly or indirectly, lowering the threshold of sensory neurons and regulate immune cell function.


OBJECTIVE
To investigate the diverse functions and molecular mechanisms of TRP channels in oral pathology and critically discuss their clinical significance and therapeutic targeting potential.


METHODS
Relevant keywords were used for research in scientific databases (Pumped, Scopus, and Science Direct). Only articles in English were included, screened, and critically analyzed. The key findings of these studies were included, along with their clinical importance.


RESULTS
Certain TRP channels were detected as key mediators of oral pathology. TRPV1 was revealed to play an important role in pain transduction in pulpits, induce inflammation, and be involved in bone resorption during periodontitis. TRPM2 activation may reduce saliva secretion in acinar salivary cells and xerostomia after head and neck radiation, while TRPV1 and TRPA1 channels mediate trigeminal nerve pain. Several TRP agonists and antagonists have been demonstrated to block pathological pathways in oral diseases along with certain compounds such as capsaicin, capsazepine, nifedipine, eugenol, thapsigargin and specific targeting techniques such as UHF-USP and Er: YAG lasers. Current TRP targeting approaches have been shown to exert beneficial effects in osteoblasts and fibroblasts proliferation, carcinoma cells' apoptosis, saliva secretion, and nociception.


CONCLUSION
TRPs play a central role in pain transduction, inflammatory responses in oral tissues, and pathological conditions of the oral mucosa, including oral squamous cell carcinoma and ulcerative mucositis.

Evangelos Evangeliou

Papers

Central Regulatory Role of Cytokines in Periodontitis and Targeting Options.

Impact of TRP Channels in Oral Pathology and Therapeutic Targeting Options: A Narrative Review.