Rheumatoid arthritis (RA), an autoimmune disease characterized by chronic inflammation of synovial tissue, is divided into two subtypes-anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA. While the pathogenic mechanisms of ACPA-positive RA are well-understood, the etiology of ACPA-negative RA remains largely unknown. The association between RA and periodontitis (PD) has been observed since the early 1900s, with the two diseases sharing common genetic and environmental risk factors that lead to the progressive destruction of bone and connective tissue. However, the associations between PD and the two subtypes of RA differ. This comprehensive review aims to provide an updated understanding of the epidemiological association between RA and PD, explore potential pathogenic mechanisms linking the two diseases, and highlight the key distinctions between the subtypes of RA and their respective associations with PD. We also discuss the possibility of early intervention or the treatment of the two diseases. Ultimately, this review aims to provide valuable insights for future research in this field.
Humans ; Arthritis, Rheumatoid/complications* ; Periodontitis/complications* ; Anti-Citrullinated Protein Antibodies/immunology* ; Risk Factors

The increasing aging population and aging-associated diseases have become a global issue for decades. People over 65 show an increased prevalence and greater severity of periodontitis, which poses threats to overall health. Studies have demonstrated a significant association between aging and the dysfunction of neutrophils, critical cells in the early stages of periodontitis, and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion. Neutrophils differentiate and mature in the bone marrow before entering the circulation; during an infection, they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens. Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues. The impacts of aging on neutrophils' chemotaxis, anti-microbial function, cell activation, and lifespan result in impaired neutrophil functions and excessive neutrophil activation, which could influence periodontitis course. We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses. We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging. This review could help us better understand the pathogenesis of periodontitis, which could offer novel therapeutic targets for periodontitis.
Humans ; Neutrophils/immunology* ; Periodontitis/immunology* ; Aging/physiology*

Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood. This condition compromises mucosal barrier integrity particularly in the gut and oral cavity. However, the mechanisms underlying this association remain unclear. This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions. Hypoxia upregulated methyltransferase-like protein 4 (METTL4) expression in platelets, resulting in N⁶-methyladenine modification of mitochondrial DNA (mtDNA). This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation, leading to cytosolic mtDNA accumulation. Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets. This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis. Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology. Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.
DNA, Mitochondrial/metabolism* ; Mouth Mucosa/pathology* ; Hypoxia/immunology* ; Methyltransferases/metabolism* ; Blood Platelets/metabolism* ; Animals ; Periodontitis/immunology* ; Humans ; Platelet Activation ; Mice

Inflammation represents a critical immune response triggered by cellular activities and inflammatory mediators following tissue damage. It plays a central role in the pathological progression of diverse diseases, including psychiatric disorders, cancer, and immunological conditions, rendering it an essential target for therapeutic intervention. Periodontitis, a prevalent oral inflammatory disease, is a leading cause of tooth loss and poses significant health challenges globally. Traditionally, inflammatory diseases such as periodontitis have been treated with systemic administration of synthetic chemicals. However, recent years have witnessed challenges, including drug resistance and microbial dysbiosis associated with these treatments. In contrast, natural products derived from Chinese medicine offer numerous benefits, such as high safety profiles, minimal side effects, innovative pharmacological mechanisms, ease of extraction, and multiple targets, rendering them viable alternatives to conventional antibiotics for treating inflammatory conditions. Numerous effective anti-inflammatory natural products have been identified in traditional Chinese medicine (TCM), including alkaloids, flavonoids, terpenoids, lignans, and other natural products that exhibit inhibitory effects on inflammation and are potential therapeutic agents. Several studies have confirmed the substantial anti-inflammatory and immunomodulatory properties of these compounds. This comprehensive review examines the literature on the anti-inflammatory effects of TCM-derived natural products from databases such as PubMed, Web of Science, and CNKI, focusing on terms like "inflammation", "periodontitis", "pharmacology", and "traditional Chinese medicine". The analysis systematically summarizes the molecular pharmacology, chemical composition, and biological activities of these compounds in inflammatory responses, alongside their mechanisms of action. This research seeks to deepen understanding of the mechanisms and biological activities of herbal extracts in managing inflammatory diseases, potentially leading to the development of promising new anti-inflammatory drug candidates. Future applications could extend to the treatment of various inflammatory conditions, including periodontitis.
Humans ; Periodontitis/immunology* ; Drugs, Chinese Herbal/chemistry* ; Medicine, Chinese Traditional ; Animals ; Anti-Inflammatory Agents/chemistry*

Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial community initiates local inflammation, over-activation of the host immune response directly activates osteoclastic activity and alveolar bone loss. Many studies have reported on the cytokine network involved in periodontitis and its crucial and pleiotropic effect on the recruitment of specific immunocytes, control of pathobionts and induction or suppression of osteoclastic activity. Nonetheless, particularities in the stimulation of pathogens in the oral cavity that lead to the specific and complex periodontal cytokine network are far from clarified. Thus, in this review, we begin with an up-to-date aetiological hypothesis of periodontal disease and summarize the roles of cytokines in the host immune response. In addition, we also summarize the latest cytokine-related therapeutic measures for periodontal disease.
Alveolar Bone Loss ; etiology ; Cytokines ; metabolism ; physiology ; Humans ; Inflammation ; Periodontal Diseases ; Periodontitis ; immunology ; microbiology ; Tumor Necrosis Factor-alpha ; physiology

Opportunistic bacteria in apical periodontitis (AP) may pose a risk for systemic dissemination. Mucosal-associated invariant T (MAIT) cells are innate-like T cells with a broad and potent antimicrobial activity important for gut mucosal integrity. It was recently shown that MAIT cells are present in the oral mucosal tissue, but the involvement of MAIT cells in AP is unknown. Here, comparison of surgically resected AP and gingival tissues demonstrated that AP tissues express significantly higher levels of Vα7.2-Jα33, Vα7.2-Jα20, Vα7.2-Jα12, Cα and tumour necrosis factor (TNF), interferon (IFN)-γ and interleukin (IL)-17A transcripts, resembling a MAIT cell signature. Moreover, in AP tissues the MR1-restricted MAIT cells positive for MR1-5-OP-RU tetramer staining appeared to be of similar levels as in peripheral blood but consisted mainly of CD4 subset. Unlike gingival tissues, the AP microbiome was quantitatively impacted by factors like fistula and high patient age and had a prominent riboflavin-expressing bacterial feature. When merged in an integrated view, the examined immune and microbiome data in the sparse partial least squares discriminant analysis could identify bacterial relative abundances that negatively correlated with Vα7.2-Jα33, Cα, and IL-17A transcript expressions in AP, implying that MAIT cells could play a role in the local defence at the oral tissue barrier. In conclusion, we describe the presence of MAIT cells at the oral site where translocation of oral microbiota could take place. These findings have implications for understanding the immune sensing of polymicrobial-related oral diseases.
Adult ; Aged ; Female ; Humans ; Immunity, Mucosal ; immunology ; Male ; Microbiota ; Middle Aged ; Mucosal-Associated Invariant T Cells ; Natural Killer T-Cells ; immunology ; Periapical Periodontitis ; microbiology ; surgery

OBJECTIVE: The aim of this study was to investigate the effect of saliva of patients with chronic periodontitis (CPD) on the differentiation, activation, and secretion of osteoclast-maturing mediators of macrophages. METHODS: A total of 40 saliva samples were collected from healthy donors (n=20) and severe periodontitis patients (n=20). Peripheral blood mononuclear cells (PBMCs) and THP-1 monocyte line cells were challenged with 15% saliva for 5 days. The phenotype, surface marker, and phagocytosis of macrophages were analyzed by flow cytometry and microscopy. Osteoclast-maturing mediators were assayed by using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: When PBMCs were treated with CPD saliva for 5 days, 61.25%±11.33% of cells were transformed into large granular cells; 86.78%±13.69% of large granular cells were identified as CD14⁺⁺CD16⁺ macrophages. When THP-1 cells were treated with CPD saliva, most cells attached to the bottom of cell culture plates, thereby exhibiting macrophage morphology and releasing additional osteoclast-maturing mediators. Furthermore, the phagocytosis of THP-1 cells considerably increased in the presence of CPD saliva (66.35%±9.67%) compared with medium control (33.33%±7.52%), or healthy saliva (40.71%±3.52%). CONCLUSIONS Saliva from patients with CPD can induce macrophage differentiation, activate phagocytose microorganisms, and secrete osteoclast-maturing mediators.
Cell Differentiation ; Humans ; Leukocytes, Mononuclear ; Macrophages ; Monocytes ; Periodontitis ; immunology ; Saliva

Inflammaging is the chronic, systematic, and controllable upregulation of a pro-inflammation state with advancing age. Chronic low-grade inflammation accompanied by sustained stimuli is correlated with various age-related diseases (ARDs). Recent studies on ARDs have prompted further research interest in the inner mechanisms underlying inflammaging to establish prevention and treatment plans for inflammatory diseases. In this article, we discuss inflammaging and its significant role in periodontitis.
Aging ; Humans ; Inflammation ; Periodontitis ; immunology

BACKGROUNDIncreasing evidence supports an association between periodontitis and systemic diseases. Leptin is involved both in the energy metabolism and inflammatory processes and is suggested to be a link between periodontal infection and systemic health. The present study aimed to evaluate the peripheral leptin concentration in patients with aggressive periodontitis (AgP) and to explore the relationship between leptin and systemic inflammation.

METHODSNinety patients with AgP visiting the Clinic of the Periodontology Department, Peking University School and Hospital of Stomatology between July 2001 and May 2006, and 44 healthy controls (staff and student volunteers in the same institute) were recruited. Plasma levels of leptin and inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay. Correlation and multiple linear regression analysis were performed to analyze the association between plasma leptin level and other variables.

RESULTSPlasma leptin level of AgP group was significantly higher than that of the control group (19.7 ± 4.4 ng/ml vs. 7.5 ± 1.3 ng/ml, P < 0.01). After controlling for age, gender, and body mass index, positive correlation was observed between plasma leptin concentration and log-transformed levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α and CRP), and the partial correlation coefficients ranged from 0.199 to 0.376 (P < 0.05). Log-transformed IL-1β and IL-6 levels entered the final regression model (standardized β were 0.422 and 0.461 respectively, P < 0.01).

CONCLUSIONSElevated plasma leptin concentration may be associated with increased systemic levels of inflammatory markers in AgP patients.

Adolescent ; Adult ; Aggressive Periodontitis ; blood ; immunology ; C-Reactive Protein ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Interleukin-6 ; blood ; Leptin ; blood ; Male ; Middle Aged ; Tumor Necrosis Factor-alpha ; blood ; Young Adult

This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the alpha1-adrenergic receptor (alpha1-AR) and beta2-adrenergic receptor (beta2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of alpha1-AR and beta2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1beta, IL-6 and IL-8 were detected after pretreatment with the alpha1/beta2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, alpha1-AR and beta2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of alpha1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of alpha1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1beta, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an alpha1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.
Adrenergic alpha-1 Receptor Antagonists/*therapeutic use ; Animals ; Cells, Cultured ; Cytokines/immunology ; Fibroblasts/immunology/pathology ; Humans ; Lipopolysaccharides/administration & dosage/immunology ; Male ; Periodontal Ligament/cytology/immunology/pathology ; Periodontitis/*drug therapy/*etiology/immunology/pathology ; Phentolamine/*therapeutic use ; Rats ; Rats, Wistar ; Receptors, Adrenergic, alpha-1/analysis/*immunology ; Signal Transduction/drug effects ; *Stress, Physiological/drug effects ; Tyrosine 3-Monooxygenase/analysis/immunology