Editorial: Community series in Unveiling Immunological Mechanisms of Periodontal Disease

Pedro Paulo Chaves de Souza ^1* Teun J. De Vries ^2*

• ¹ Universidade Federal de Goiás, Goiânia, Brazil
• ² Academic Centre for Dentistry Amsterdam, VU Amsterdam, Amsterdam, Netherlands

It is still a scientific challenge to study immunological mechanisms of complex diseases associated with the inflamed periodontium, the tissues that surround our teeth. Periodontitis, a chronic inflammatory disease that is associated with bone loss, is particularly difficult to investigate due to its alternating active and silent phases. The dysbiotic biofilm that is associated with the disease, may vary between patients, stage of the disease and sample sites. Mouse models may contribute mechanistically but may have shortcomings in mimicking dysbiosis. Understanding patient's cohort characteristics may help further characterize inflammation-related parameters.The present series is the sequential series of the previous one on "Unveiling Immunological Mechanisms of Periodontal Disease" (1). Compared to the previous series, the present one has shifted towards themes that were not addressed three years ago and probably reflect the novel tools that are available through knowledge on the genome and emerging techniques such as single cell RNA sequencing (scRNA-seq). This collection of 10 articles has contributed to the following themes.Understanding the cellular and molecular mechanisms driving periodontal inflammation and tissue destruction remains the basis of periodontal research. Advances in systems biology and cutting-edge transcriptomic technologies have enabled researchers to dissect the complex interactions between immune cells, stromal cells, and microbial communities in the periodontium. The following studies exemplify how cell biological models are shedding light on the immunomodulatory roles of specific cell populations and pathways, offering new insights into the pathogenesis of periodontitis and potential therapeutic targets.The study by Kim et al. unveils a pivotal role for ICAM1+ gingival fibroblasts as immunomodulatory sentinels in periodontal inflammation. Through integrative analysis of human scRNA-seq datasets, the authors demonstrate that ICAM1, the cell-cell adhesion molecule with which fibroblasts may interact with immune cells, marks a fibroblast subset expressing an inflammatory signature. This population orchestrate macrophage recruitment via CCL2, enabling efferocytosis to resolve neutrophilic inflammation, a process critical for mitigating tissue destruction. These findings redefine stromal-immune crosstalk in periodontal niches and highlight ICAM1+ fibroblasts as therapeutic targets to modulate inflammation-driven bone loss. Zhao et al. examine the role of the mechanosensitive ion channel Piezo1 in gingival destruction linked to periodontitis. Piezo1 expression is upregulated in the gingival tissues of periodontitis patients and drives macrophage polarization toward the M1 phenotype, leading to pro-inflammatory cytokine production and activation of MMPs, contributing to tissue destruction. The study suggests that inhibiting Piezo1 may reduce inflammation and collagen degradation, presenting a potential therapeutic target for periodontitis. Hu et al. investigate the role of miR-199a-5p in bone regeneration during apical periodontitis (AP), a disease marked by periapical inflammation and alveolar bone loss. Using transcriptomic analysis of clinical samples, the authors identified miR-199a-5p as significantly downregulated in AP tissues. Functional studies revealed that miR-199a-5p overexpression enhanced the proliferation and osteogenic differentiation of human stem cells from the apical papilla (hSCAPs), while its inhibition suppressed these processes. Mechanistically, miR-199a-5p targets IFIT2, a gene linked to type I interferon signaling, thereby alleviating its suppressive effects on osteogenesis. Furthermore, in vivo experiments demonstrated that hSCAPs overexpressing miR-199a-5p, when loaded onto β-tricalcium phosphate scaffolds, significantly enhanced ectopic bone formation in mice. These findings underscore miR-199a-5p as a critical regulator of bone repair in AP.Together, these studies highlight the multifaceted roles of fibroblasts, mechanosensitive pathways, and miRNAs in periodontal inflammation and bone remodeling, offering new avenues for therapeutic intervention.Periodontitis may elicit antibody production against proteins of periodontal pathogens such as Porphyromonis gingivalis. A large, well-characterized cohort study such as the PerioGene North casecontrol study could determine whether antibodies against periodontal pathogens such as antiarginine gingipains (Rgp), are associated with disease progression. Serum-Rgp IgG levels were clearly elevated in periodontitis patients compared to controls, and were even higher in patients with a high inflammation grade and with alveolar bone loss Kindstedt E et al.To further explore the interactions of periodontal pathogenes with the human immune system, Irwandi et al propose the use of the skin blister model to study the immunopathogenesis of periodontal disease. This model offers a controlled environment to explore localized host-pathogen interactions, bridging the gap between ex vivo studies and clinical observations, further advancing our understanding of the systemic links to periodontal inflammation.Mendelian randomization is a relatively novel method that allows to access causal relationships between risk factors and health outcomes using genetic variants as instruments to infer causal effects (2). The current issue describes roles of tumor necrosis factor-receptor 1 TNF-α Alayash H et al., interleukin-6 signaling Nolde M et al. and telomere length Hu J et al.. Where the first study did not find a relation between TNF-receptor inhibition and periodontits Alaysh H et la., the interleukin study demonstrated that downregulation of IL-6 signaling based on genetic information was associated with lower odds of periodontitis. As we grow older, telomeres shorten (3). Since periodontitis increases with age, one would expect that shorter telomere length correlates with periodontal disease. Hu J et al. showed indeed a reverse causal relationship, with shorter telomeres being linked to a higher risk of periodontitis, but no additional effect of telomere length and periodontitis when corrected for age.To conclude, this issue further contains two state-of-the-art reviews. Novel research shows that chewing is beneficial for the aging periodontium and could help individuals to maintain their teeth even at a high age (4). Mechanical forces may affect periodontal health through multiple mechanisms. Mechanical forces can influence soft and hard tissue metabolism. Forces that are too high may damage the periodontium or result in irreversible inflammation. In their review, Wang T et al., describe the effect of mechanical forces on the parameters of the periodontium.The review by Zhang et al. highlights how emerging omics tools, such as RNAseq are revealing dynamic shifts in epithelial, stromal, and immune cell populations that drive inflammation and bone resorption, revolutionizing our understanding on immunopathology. However, as exemplified across this series, these discoveries require rigorous experimental validation. Integrating multi-omics approaches with mechanistic models and clinical cohorts will be critical to unraveling the heterogeneity of dysbiotic biofilms and host responses. Together, this synergy of technologies and validation frameworks promises to advance precision therapies, addressing both the oral and systemic dimensions of periodontal disease.