Cytokines in gingivitis and periodontitis: from pathogenesis to therapeutic targets.

Chronic inflammatory processes in the oral mucosa and periodontitis are common disorders caused by microflora and microbial biofilms. These factors activate both the innate and adaptive immune systems, leading to the production of pro-inflammatory cytokines. Cytokines are known to play a crucial role in the pathogenesis of gingivitis and periodontitis and have been proposed as biomarkers for diagnosis and follow-up of these diseases. They can activate immune and stromal cells, leading to local inflammation and tissue damage. This damage can include destruction of the periodontal ligaments, gingiva, and alveolar bone. Studies have reported increased local levels of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta), tumor necrosis factor (TNF), IL-6, IL-17, and IL-23, in patients with periodontitis. In experimental models of periodontitis, TNF and the IL-23/IL-17 axis play a pivotal role in disease pathogenesis. Inactivation of these pro-inflammatory pathways through neutralizing antibodies, genetic engineering or IL-10 function has been demonstrated to reduce disease activity. This review discusses the role of cytokines in gingivitis and periodontitis, with particular emphasis on their role in mediating inflammation and tissue destruction. It also explores new therapeutic interventions that offer potential for research and clinical therapy in these chronic inflammatory diseases.

The role of NF-kappaB in the inflammatory processes related to dental caries, pulpitis, apical periodontitis, and periodontitis-a narrative review.

Tooth-related inflammatory disorders, including caries, pulpitis, apical periodontitis (AP), and periodontitis (PD), are primarily caused by resident oral microorganisms. Although these dental inflammatory conditions are typically not life-threatening, neglecting them can result in significant complications and greatly reduce an individual's quality of life. Nuclear factor κB (NF-κB), a family formed by various combinations of Rel proteins, is extensively involved in inflammatory diseases and even cancer. This study reviews recent data on NF-κB signaling and its role in dental pulp stem cells (DPSCs), dental pulp fibroblasts (DPFs), odontoblasts, human periodontal ligament cells (hPDLCs), and various experimental animal models. The findings indicate that NF-κB signaling is abnormally activated in caries, pulpitis, AP, and PD, leading to changes in related cellular differentiation. Under specific conditions, NF-κB signaling occasionally interacts with other signaling pathways, affecting inflammation, bone metabolism, and tissue regeneration processes. In summary, data collected over recent years confirm the central role of NF-κB in dental inflammatory diseases, potentially providing new insights for drug development targeting NF-κB signaling pathways in the treatment of these conditions. Keywords: NF-κB, dental caries, pulpitis, apical periodontitis, periodontitis.

Role of CD86 on granulocyte in mediating the effect of Genus Roseburia on periodontitis.

OBJECTIVES: This study aimed to explore the causal link between the gut microbiota and periodontitis, and to delineate and quantify the intermediary role of immune cells, so as to provide new insights into the pathogenesis, prevention and treatment of periodontitis. MATERIALS AND METHODS: We employed a two-sample Mendelian randomization (MR) approach to analyze the genetic predictors of gut microbiota composition (covering 412 gut microbiota taxa and functions) and periodontitis (involving 4,784 cases and 272,252 controls) derived from genome-wide association study (GWAS) datasets. A subsequent two-step MR analysis was conducted to evaluate the extent to which immune cell traits (encompassing 731 immune cell characteristics) mediate the influence of gut microbiota on periodontitis risk. RESULTS: Our analysis implicated nine gut microbiota taxa as causal factors in periodontitis susceptibility (p < 0.05). Notably, the Genus Roseburia was identified as exerting a protective effect against periodontitis, partially mediated through the upregulation of CD86 expression on granulocytes, with an 8.15% mediation effect observed. CONCLUSIONS: Our findings establish a causal relationship between the gut microbiota and periodontitis, highlighting the protective role of Roseburia against this condition. A notable proportion of this protective effect is mediated via the upregulation of CD86 on granulocytes. CLINICAL RELEVANCE: It can provide new ideas for the pathogenesis, prevention and treatment for periodontitis through exploring the causal link between the gut microbiota and periodontitis, and describing and quantifying the intermediary role of immune cells.

Sclerostin antibody corrects periodontal disease in type 2 diabetic mice.

Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications in the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDLs), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for 4 weeks, starting 4 weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.

High concentrations of NaF aggravate periodontitis by promoting M1 polarization in macrophages.

High-concentration fluoride treatment is commonly used to prevent dental caries in the oral cavity, and fluorine-containing protective paint is used to alleviate common root sensitivity symptoms in patients with periodontitis after periodontal treatment. Recent studies have confirmed its safe use in normal oral environments. However, whether fluoride treatment affects the progression of periodontitis in an inflammatory microenvironment remains unclear. Immunometabolism is crucial for maintaining bone regeneration and repair in periodontitis, and the precise regulation of macrophage polarisation is crucial to this process. Fluoride can influence the immune microenvironment of bone tissue by regulating immune metabolic processes. Herein, we investigated the effects of high concentrations of sodium fluoride (NaF) on periodontal tissues. We examined the expression of osteogenic and M1/M2 macrophage polarisation markers and glucose metabolism in macrophages. RNA sequencing was used to study differentially expressed genes related to M1 polarisation and glucose metabolism in treated macrophages. The results showed that NaF indirectly affects human periodontal ligament cells (hPDLCs), aggravating bone loss, tissue destruction, and submandibular lymph node drainage. Furthermore, NaF promoted glycolysis in macrophages and M1 polarisation while inhibiting osteogenic differentiation. These findings suggest that NaF has a direct effect on hPDLCs. Moreover, we found that high concentrations of NaF stimulated M1 polarisation in macrophages by promoting glycolysis. Overall, these results suggest that M1 macrophages promote the osteoclastic ability of hPDLCs and inhibit their osteogenic ability, eventually aggravating periodontitis. These findings provide important insights into the mechanism of action of NaF in periodontal tissue regeneration and reconstruction, which is critical for providing appropriate recommendations for the use of fluoride in patients with periodontitis.

Salivary IL-1ß, IL-6, and IL-10 Are Key Biomarkers of Periodontitis Severity.

To explore severity and progression biomarkers, we examined the clinical relevance of multiple cytokines and mediators involved in the inflammatory response in periodontitis. A cohort of 68 patients was enrolled in the study and periodontal status assessed by the current classification of periodontal diseases. Immune mediators present in saliva, of both patients and healthy controls, were quantified using a Legendplex-13 panel. Clinic parameters were significantly higher in PD patients compared with HC, with a strong significant association with the disease severity (stage) (p < 0.001), but not with progression (grade). The panel of immune mediators evidenced elevated levels of pro-inflammatory cytokines IL-6 and IL-1ß as disease established (p < 0.01). IL-1ß/IL-1RA ratio was increased in PD patients, being associated with disease stage. An anti-inflammatory response was spotted by higher IL-10. Lower levels of IL-23 and IP-10 were associated with disease severity. No significant statistical differences were found by grade classification. Moreover, salivary IL-1ß and IL-6 exhibited significant positive correlations with several clinical measurements (PI, BOP, PPD, CAL), while IP-10 showed a statistical negative correlation with BOP, PPD, and CAL. These insights highlight the complexity of the periodontitis inflammatory network and the potential of cytokines as biomarkers for refined diagnostic and therapeutic strategies.

Exploration of the shared diagnostic genes and mechanisms between periodontitis and primary Sjögren's syndrome by integrated comprehensive bioinformatics analysis and machine learning.

BACKGROUND: Accumulating evidence has showed a bidirectional link between periodontitis (PD) and primary Sjögren's syndrome (pSS), but the mechanisms of their occurrence remain unclear. Hence, this study aimed to investigate the shared diagnostic genes and potential mechanisms between PD and pSS using bioinformatics methods. METHODS: Gene expression data for PD and pSS were acquired from the Gene Expression Omnibus (GEO) database. Differential expression genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) were utilized to search common genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to explore biological functions. Three machine learning algorithms (least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF)) were used to further identify shared diagnostic genes, and these genes were assessed via receiver operating characteristic (ROC) curves in discovery and validation datasets. CIBERSORT was employed for immune cell infiltration analysis. Transcription factors (TFs)-genes and miRNAs-genes regulatory networks were conducted by NetworkAnalyst. Finally, relevant drug targets were predicted by DSigDB. RESULTS: Based on DEGs, 173 overlapping genes were obtained and primarily enriched in immune- and inflammation-related pathways. WGCNA revealed 34 common disease-related genes, which were enriched in similar biological pathways. Intersecting the DEGs with WGCNA results yielded 22 candidate genes. Moreover, three machine learning algorithms identified three shared genes (CSF2RB, CXCR4, and LYN) between PD and pSS, and these genes demonstrated good diagnostic performance (AUC>0.85) in both discovery and validation datasets. The immune cell infiltration analysis showed significant dysregulation in several immune cell populations. Regulatory network analysis highlighted that WRNIP1 and has-mir-155-5p might be pivotal co-regulators of the three shared gene expressions. Finally, the top 10 potential gene-targeted drugs were screened. CONCLUSION: CSF2RB, CXCR4, and LYN may serve as potential biomarkers for the concurrent diagnosis of PD and pSS. Additionally, we identified common molecular mechanisms, TFs, miRNAs, and candidate drugs between PD and pSS, which may provide novel insights and targets for future research on the pathogenesis, diagnosis, and therapy of both diseases.

Natural compound phloretin restores periodontal immune homeostasis via HIF-1α-regulated PI3K/Akt and glycolysis in macrophages.

Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis.

Therapeutic delivery of CCL2 modulates immune response and restores host-microbe homeostasis.

Many chronic inflammatory diseases are attributed to disturbances in host-microbe interactions, which drive immune-mediated tissue damage. Depending on the anatomic setting, a chronic inflammatory disease can exert unique local and systemic influences, which provide an exceptional opportunity for understanding disease mechanism and testing therapeutic interventions. The oral cavity is an easily accessible environment that allows for protective interventions aiming at modulating the immune response to control disease processes driven by a breakdown of host-microbe homeostasis. Periodontal disease (PD) is a prevalent condition in which quantitative and qualitative changes of the oral microbiota (dysbiosis) trigger nonresolving chronic inflammation, progressive bone loss, and ultimately tooth loss. Here, we demonstrate the therapeutic benefit of local sustained delivery of the myeloid-recruiting chemokine (C-C motif) ligand 2 (CCL2) in murine ligature-induced PD using clinically relevant models as a preventive, interventional, or reparative therapy. Local delivery of CCL2 into the periodontium inhibited bone loss and accelerated bone gain that could be ascribed to reduced osteoclasts numbers. CCL2 treatment up-regulated M2-macrophage and downregulated proinflammatory and pro-osteoclastic markers. Furthermore, single-cell ribonucleic acid (RNA) sequencing indicated that CCL2 therapy reversed disease-associated transcriptomic profiles of murine gingival macrophages via inhibiting the triggering receptor expressed on myeloid cells-1 (TREM-1) signaling in classically activated macrophages and inducing protein kinase A (PKA) signaling in infiltrating macrophages. Finally, 16S ribosomal ribonucleic acid (rRNA) sequencing showed mitigation of microbial dysbiosis in the periodontium that correlated with a reduction in microbial load in CCL2-treated mice. This study reveals a novel protective effect of CCL2 local delivery in PD as a model for chronic inflammatory diseases caused by a disturbance in host-microbe homeostasis.

Periodontitis is an immune-related adverse event associated with immune checkpoint inhibitors: A multi-center cohort study.

Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs) across various organ systems including oral health complications such as dry mouth and stomatitis. In this study, we aimed to determine the risk of periodontitis among patients on immune checkpoint inhibitors (ICIs) and to test the associations between ICI-associated periodontitis and other immune-related adverse events (irAEs). We performed a retrospective cohort study involving adult cancer patients between January 2010 and November 2021. Patients on an ICI were propensity score-matched to patients not on an ICI. The primary outcome was the occurrence of periodontitis. ICIs included programmed cell death 1 (PD-1) inhibitors programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. The risk of periodontitis following ICI use was derived through a Cox proportional hazard model and Kaplan-Meier survival analysis. Overall, 868 patients on an ICI were matched to patients not on an ICI. Among the ICI cohort, 41 (4.7 %) patients developed periodontitis. The incidence rate of periodontitis was significantly higher in patients on an ICI than in patients not on an ICI (55.3 vs 25.8 per 100 patient-years, incidence rate ratio = 2.14, 95 % CI = 1.38-3.33). Both the use of PD-L1 inhibitors (multivariate HR = 2.5, 95%CI = 1.3-4.7) and PD-1 inhibitors (multivariate HR = 2.0, 95%CI = 1.2-3.2) were associated with the risk of periodontitis. The presence of immune-related periodontitis was associated with better overall survival (not reached vs 17 months, log-rank p-value<0.001), progression-free survival (14.9 vs 5.6 months, log-rank p-value = 0.01), and other concomitant immune-related cutaneous adverse events. In conclusion, ICI was associated with an increased risk of periodontitis. Immune-related periodontitis as an irAE was associated with better cancer survival and concomitant cutaneous irAEs.

The role of WTAP in regulating macrophage-mediated osteoimmune responses and tissue regeneration in periodontitis.

Periodontitis, delineated by the destruction of structures that support teeth, is predominantly propelled by intricate immune responses. Immunomodulatory treatments offer considerable promise for the management of this ailment; however, the modulation of the periodontal immune microenvironment to facilitate tissue regeneration presents a substantial biomedical challenge. Herein, our study investigates the role of Wilms' tumor 1-associating protein (WTAP), a critical m6A methyltransferase, in the immunomodulation of periodontitis and assesses its viability as a therapeutic target. We observed heightened expression of WTAP in macrophages extracted from gingival tissues impacted by periodontitis, with a strong association with M1 polarization. Via loss-of-function experiments, we demonstrated that diminishing WTAP expression precipitates a transition from M1 to M2 macrophage phenotypes amidst inflammatory conditions, thus improving the periodontal immune landscape. Further, RNA sequencing and indirect co-culture assays indicated that suppressing of WTAP expression modulates osteoimmune responses and enhances the osteogenic differentiation of bone marrow stromal cells. The local deployment of adeno-associated virus-shWTAP in murine models of periodontitis robustly validated the therapeutic promise of targeting WTAP in this disease. Collectively, our findings highlight the crucial role of WTAP in orchestrating macrophage-mediated osteoimmune responses and tissue regeneration in periodontitis, proposing novel avenues for immunotherapeutic interventions in its treatment.

Advances and challenges in the development of periodontitis vaccines: A comprehensive review.

Periodontitis is a prevalent polymicrobial disease. It damages soft tissues and alveolar bone, and causes a significant public-health burden. Development of an advanced therapeutic approach and exploration of vaccines against periodontitis hold promise as potential treatment avenues. Clinical trials for a periodontitis vaccine are lacking. Therefore, it is crucial to address the urgent need for developing strategies to implement vaccines at the primary level of prevention in public health. A deep understanding of the principles and mechanisms of action of vaccines plays a crucial role in the successful development of vaccines and their clinical translation. This review aims to provide a comprehensive summary of potential directions for the development of highly efficacious periodontitis vaccines. In addition, we address the limitations of these endeavors and explore future possibilities for the development of an efficacious vaccine against periodontitis.

[Research progress in dual immune regulation of neutrophils in periodontal inflammation].

Periodontitis is a chronic inflammatory condition of the periodontal tissues triggered by bacterial biofilm, leading to manifestations such as gingival bleeding, tooth mobility, and eventual exfoliation. Neutrophils exhibit a dual role throughout the course of periodontitis, both in defense against pathogens and in potentially detrimental effects on periodontal tissues. This article elucidates the intricate mechanisms underlying the dual functions of neutrophils in periodontitis, including respiratory burst, neutrophil extracellular traps (NETs) formation, degranulation, and phagocytosis. By providing a comprehensive understanding of neutrophils involvement in periodontitis, this study aims to empower clinicians with insights into the pathogenesis of periodontitis, thereby fostering novel strategies for its prevention and treatment.

Rational design of multifunctional hydrogels targeting the microenvironment of diabetic periodontitis.

Periodontitis is a chronic inflammatory disease and is the primary contributor to adult tooth loss. Diabetes exacerbates periodontitis, accelerates periodontal bone resorption. Thus, effectively managing periodontitis in individuals with diabetes is a long-standing challenge. This review introduces the etiology and pathogenesis of periodontitis, and analyzes the bidirectional relationship between diabetes and periodontitis. In this review, we comprehensively summarize the four pathological microenvironments influenced by diabetic periodontitis: high glucose microenvironment, bacterial infection microenvironment, inflammatory microenvironment, and bone loss microenvironment. The hydrogel design strategies and latest research development tailored to the four microenvironments of diabetic periodontitis are mainly focused on. Finally, the challenges and potential solutions in the treatment of diabetic periodontitis are discussed. We believe this review will be helpful for researchers seeking novel avenues in the treatment of diabetic periodontitis.

Changing behind the scenes.

Th17 cell plasticity is associated with pathogenicity in chronic inflammation. In a model of periodontitis, McClure et al. (https://doi.org/10.1084/jem.20232015) describe location-dependent divergence in Th17 plasticity, with surprisingly limited conversion in inflamed gingiva but emergence of protective exTh17-TfH cells in draining LN that enhance protective antibody.

Investigating the Interplay: Periodontal Disease and Type 1 Diabetes Mellitus-A Comprehensive Review of Clinical Studies.

Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from the interplay between oral microbiota and the host immune response. A comprehensive search of studies published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population.

Elevated neutrophil extracellular trap levels in periodontitis: Implications for keratinization and barrier function in gingival epithelium.

AIM: To explore the levels of neutrophil extracellular traps (NETs) in patients with periodontitis and examine their effects on keratinization, barrier function of human gingival keratinocytes (HGKs) and the associated mechanisms. MATERIALS AND METHODS: Saliva, gingival crevicular fluid (GCF), clinical periodontal parameters and gingival specimens were collected from 10 healthy control subjects and 10 patients with stage II-IV periodontitis to measure the NET levels. Subsequently, mRNA and protein levels of keratinization and barrier indicators, as well as intracellular calcium and epithelial barrier permeability, were analysed in HGKs after NET stimulation. RESULTS: The study showed that NET levels significantly elevated in patients with periodontitis, across multiple specimens including saliva, GCF and gingival tissues. Stimulation of HGKs with NETs resulted in a decrease in the expressions of involucrin, cytokeratin 10, zonula occludens 1 and E-cadherin, along with decreased intracellular calcium levels and increased epithelial barrier permeability. Furthermore, the inhibition of keratinization by NETs is ERK-KLF4-dependent. CONCLUSIONS: This study indicates that NETs impair the barrier function of HGKs and suppress keratinization through ERK/KLF4 axis. These findings provide potential targets for therapeutic approaches in periodontitis to address impaired gingival keratinization.

Periodontal inflammation as a potential driver of HIV low level viremia.

HIV can be successfully suppressed to undetectable levels by antiretroviral therapy (ART) in most people with HIV (PWH). However, a small proportion continues to have persistent low-level viremia (LLV) during ART. A presumed source of LLV is production or replication from viral reservoirs, which are maintained in the presence of ART. It is unknown whether the oral cavity can be considered an HIV reservoir. As periodontal inflammation is a common problem in PWH, we hypothesize that periodontal inflammation in the oral cavity activates (latently) infected cells and thus might be associated with LLV. We included 11 individuals with HIV LLV, and compared HIV-RNA levels in saliva and plasma at baseline and at week 24 after switch of ART. We compared the LLV-group at baseline with 11 age-matched controls with suppressed viremia. To investigate the severity of periodontitis we used Periodontal Inflamed Surface Areas (PISA) by measuring probing depth, gingival recession, bleeding on probing and clinical attachment level. Severity of periodontitis was classified according to the CDC-AAP case definition. Additional insights in periodontal inflammation were obtained by comparing immune activation markers and the presence of periodontal pathogens. In four individuals of the LLV group, residual levels of HIV-RNA were detected in saliva at baseline (N = 1) or at week 24 (N = 2) or both (N = 1). Of the four individuals with LLV, three had residual levels of HIV-RNA in saliva. All 22 individuals had moderate to severe periodontitis. PISA was not significantly different between cases with LLV and controls. Similarly, periodontal pathogens were frequently observed in both groups. Total activated HLA-DR+CD38+ CD4+ cells and CD8+ cells were significantly higher in the LLV group than in the control group (p = <0.01). No immune markers were associated with LLV. In conclusion, periodontal inflammation is an unlikely driver of HIV LLV compared to HIV suppressed individuals.

Modulation of allograft immune responses by Porphyromonas gingivalis lipopolysaccharide administration in a rat model of kidney transplantation.

Periodontitis is a chronic inflammatory disease that affects the periodontal tissues. Although it is associated with various systemic diseases, the impact of periodontitis on kidney transplantation (KT) outcomes, particularly allograft rejection, remains unclear. This study investigated the effect of periodontitis on transplant immunity, specifically examining Porphyromonas gingivalis-derived lipopolysaccharide (LPS-PG). In vitro experiments revealed that LPS-PG increased regulatory T cells (Tregs) in Lewis rat spleen cells. In a mixed lymphocyte reaction assay, concentrations of interferon-γ, indicative of alloreactivity, were lower than in controls when LPS-PG was added to the culture and when LPS-PG-administered Lewis rat spleen cells were used as responders. In a rat KT model, LPS-PG administration to recipients promoted mild tubulitis and low serum creatinine and blood urea nitrogen levels 5 days post-KT compared with PBS-administered controls. Furthermore, LPS-PG-administered recipients had an elevated Treg proportion in their peripheral blood and spleen cells, and increased infiltrating Tregs in kidney allografts, compared with controls. The elevated Treg proportion in peripheral blood and spleen cells had a significant negative correlation with serum creatinine, suggesting elevated Tregs modulated allograft rejection. These findings suggest that periodontitis might modulate alloimmune reactivity through LPS-PG and Tregs, offering insights to refine immunosuppressive strategies for KT recipients.

Toll-like receptor 4 deficiency affects the balance of osteoclastogenesis and osteoblastogenesis in periodontitis.

Toll-like receptor 4 (TLR4) acts as a double-edged sword in the occurrence and development of periodontitis. While the activation of TLR4 in macrophages aids in clearing local pathogens, it can also disrupt innate immune responses, upsetting microecological balance and accelerating the destruction of periodontal bone tissues. To date, the effects of TLR4 on osteogenesis and osteoclastogenesis in periodontitis have not been comprehensively studied. In this study, we investigated the development of periodontitis in the Tlr4-/- mice by ligating their second molars with silk threads. Compared to wild-type (WT) mice, Tlr4-/- mice demonstrated increased resistance to periodontitis-associated bone destruction, as evidenced by decreased bone resorption and enhanced bone regeneration. Mechanistically, the deletion of Tlr4 not only inhibited osteoclast formation by reducing the expression of NFATc1, CTSK and TRAP, but also enhanced osteogenic abilities through increased expression of OCN, OPN and RUNX2. In conclusion, TLR4 tips the balance of osteoclastogenesis and osteogenesis, thereby promoting periodontal bone destruction in periodontitis.