RESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
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Hematopoyesis Clonal , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Periodontitis , Animales , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Ratones , Hematopoyesis Clonal/genética , Humanos , Periodontitis/genética , Periodontitis/patología , Mutación , Masculino , Femenino , Inflamación/genética , Inflamación/patología , Osteoclastos/metabolismo , Ratones Endogámicos C57BL , Adulto , Interleucina-17/metabolismo , Interleucina-17/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Hematopoyesis/genética , Osteogénesis/genética , Células Madre Hematopoyéticas/metabolismo , Resorción Ósea/genética , Resorción Ósea/patología , Persona de Mediana EdadRESUMEN
The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis.
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Inmunidad Mucosa , Mucosa Bucal/citología , Mucosa Bucal/inmunología , Neutrófilos/citología , Adulto , Células Epiteliales/citología , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Encía/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Microbiota , Células Mieloides/citología , Periodontitis/genética , Periodontitis/inmunología , Periodontitis/patología , Análisis de la Célula Individual , Células del Estroma/citología , Linfocitos T/citologíaRESUMEN
The precise mechanism by which oral infection contributes to the pathogenesis of extra-oral diseases remains unclear. Here, we report that periodontal inflammation exacerbates gut inflammation in vivo. Periodontitis leads to expansion of oral pathobionts, including Klebsiella and Enterobacter species, in the oral cavity. Amassed oral pathobionts are ingested and translocate to the gut, where they activate the inflammasome in colonic mononuclear phagocytes, triggering inflammation. In parallel, periodontitis results in generation of oral pathobiont-reactive Th17 cells in the oral cavity. Oral pathobiont-reactive Th17 cells are imprinted with gut tropism and migrate to the inflamed gut. When in the gut, Th17 cells of oral origin can be activated by translocated oral pathobionts and cause development of colitis, but they are not activated by gut-resident microbes. Thus, oral inflammation, such as periodontitis, exacerbates gut inflammation by supplying the gut with both colitogenic pathobionts and pathogenic T cells.
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Colitis/patología , Enterobacter/fisiología , Microbioma Gastrointestinal , Klebsiella/fisiología , Boca/microbiología , Animales , Colitis/microbiología , Colon/microbiología , Colon/patología , Modelos Animales de Enfermedad , Enterobacter/aislamiento & purificación , Femenino , Inflamasomas/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucina-1beta/metabolismo , Klebsiella/aislamiento & purificación , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodontitis/microbiología , Periodontitis/patología , Células Th17/citología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Integrin ß6 (ITGB6), a member of the integrin family of proteins, is only present in epithelial tissues and frequently associates with integrin subunit αv to form transmembrane heterodimers named integrin αvß6. Importantly, ITGB6 determines αvß6 expression and availability. In addition to being engaged in organ fibrosis, ITGB6 is also directly linked to the emergence of cancer, periodontitis, and several potential genetic diseases. Therefore, it is of great significance to study the molecular-biological mechanism of ITGB6, which could provide novel insights for future clinical diagnosis and therapy. This review introduces the structure, distribution, and biological function of ITGB6. This review also expounds on ITGB6-related diseases, detailing the known biological effects of ITGB6.
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Antígenos de Neoplasias , Fibrosis , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Fibrosis/genética , Fibrosis/metabolismo , Animales , Cadenas beta de Integrinas/metabolismo , Cadenas beta de Integrinas/genética , Integrinas/metabolismo , Integrinas/genética , Periodontitis/genética , Periodontitis/metabolismo , Periodontitis/patologíaRESUMEN
Peri-implantitis (PI) and periodontitis (PD) are common oral inflammatory diseases, which seem to exhibit critical differences in some of their molecular features. Thus, we assessed the immune cell composition of PI and PD lesions and the corresponding inflammatory profile in soft tissues and crevicular fluid. PI, PD, and control patients were recruited (nâ =â 62), and soft tissue biopsies were collected during surgery. Crevicular fluid around implant or tooth was collected. The proportions of major immune cell populations in tissues were analyzed by flow cytometry, and the inflammatory profile in tissue and crevicular fluid by a multiplex immunoassay. No significant difference was seen between PI and PD lesions in the proportions of immune cells. PI tissues showed an increased frequency of B cells in comparison with control tissues, along with higher levels of IL-1ß, TNF-α, IL-4, and BAFF in tissue and crevicular fluid. Moreover, TNF-α, IL-17A, and BAFF were higher in PI tissues, but not in PD, than in control tissues. The immune cell composition did not differ significantly between PI and PD, but an enhanced inflammatory profile was seen in PI tissue. PI lesions were enriched in B cells, and displayed increased levels of IL-1ß, TNF-α, IL-4, and BAFF in both tissue and crevicular fluid.
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Líquido del Surco Gingival , Periimplantitis , Periodontitis , Humanos , Periimplantitis/inmunología , Periimplantitis/patología , Masculino , Femenino , Persona de Mediana Edad , Periodontitis/inmunología , Periodontitis/patología , Líquido del Surco Gingival/inmunología , Interleucina-1beta/metabolismo , Interleucina-1beta/análisis , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Linfocitos B/inmunología , Interleucina-17/metabolismo , Anciano , Adulto , Interleucina-4/metabolismo , Inflamación/inmunología , Citocinas/metabolismo , Factor Activador de Células BRESUMEN
BACKGROUND AND OBJECTIVE: Progranulin (PGRN), a multifunctional growth factor, plays indispensable roles in the regulation of cancer, inflammation, metabolic diseases, and neurodegenerative diseases. Nevertheless, its immune regulatory role in periodontitis is insufficiently understood. This study attempts to explore the regulatory effects of PGRN on macrophage polarization in periodontitis microenvironment. METHODS: Immunohistochemical (IHC) and multiplex immunohistochemical (mIHC) stainings were performed to evaluate the expression of macrophage-related markers and PGRN in gingival samples from periodontally healthy subjects and periodontitis subjects. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were polarized towards M1 or M2 macrophages by the addition of LPS or IL-4, respectively, and were treated with or without PGRN. Real-time fluorescence quantitative PCR (qRT-PCR), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), and flow cytometry were used to determine the expressions of M1 and M2 macrophage-related markers. Co-immunoprecipitation was performed to detect the interaction between PGRN and tumor necrosis factor receptor 2 (TNFR2). Neutralizing antibody was used to block TNFR2 to confirm the role of TNFR2 in PGRN-mediated macrophage polarization. RESULTS: The IHC and mIHC staining of human gingival slices showed a significant accumulation of macrophages in the microenvironment of periodontitis, with increased expressions of both M1 and M2 macrophage markers. Meanwhile, PGRN was widely expressed in the gingival tissue of periodontitis and co-expressed mainly with M2 macrophages. In vitro experiments showed that in RAW264.7 cells and BMDMs, M1 markers (CD86, TNF-α, iNOS, and IL-6) substantially decreased and M2 markers (CD206, IL-10, and Arg-1) significantly increased when PGRN was applied to LPS-stimulated macrophages relatively to LPS stimulation alone. Besides, PGRN synergistically promoted IL-4-induced M2 markers expression, such as CD206, IL-10, and Arg1. In addition, the co-immunoprecipitation result showed the direct interaction of PGRN with TNFR2. mIHC staining further revealed the co-localization of PGRN and TNFR2 on M2 macrophages (CD206+). Blocking TNFR2 inhibited the regulation role of PGRN on macrophage M2 polarization. CONCLUSIONS: In summary, PGRN promotes macrophage M2 polarization through binding to TNFR2 in both pro- and anti-inflammatory periodontal microenvironments.
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Polaridad Celular , Macrófagos , Periodontitis , Progranulinas , Receptores Tipo II del Factor de Necrosis Tumoral , Periodontitis/metabolismo , Periodontitis/patología , Macrófagos/metabolismo , Humanos , Animales , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Progranulinas/metabolismo , Ratones , Células RAW 264.7 , Encía/metabolismo , Encía/patología , Masculino , Femenino , Adulto , Activación de Macrófagos , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BLRESUMEN
Formation of granulation tissue is a fundamental phase in periodontal wound healing with subsequent maturation leading to regeneration or repair. However, persistently inflamed granulation tissue presents in osseous defects as a result of periodontitis and is routinely disrupted and discarded with non-surgical and surgical therapy to facilitate wound healing or improve chances of regeneration. Histological assessment suggests that granulation tissue from periodontitis-affected sites is effectively a chronic inflammatory tissue resulting from impaired wound healing due to persistence of bacterial dysbiotic bioflim. Nevertheless, the immunomodulatory potential and stem cell characteristics in granulation tissue have also raised speculation about the tissue's regenerative potential. This has led to the conception and recent implementation of surgical techniques which preserve granulation tissue with the intention of enhancing innate regenerative potential and improve clinical outcomes. As knowledge of fundamental cellular and molecular functions regulating periodontitis-affected granulation tissue is still scarce, this review aimed to provide a summary of current understanding of granulation tissue in the context of periodontal wound healing. This may provide new insights into clinical practice related to the management of granulation tissue and stimulate further investigation.
Asunto(s)
Tejido de Granulación , Cicatrización de Heridas , Tejido de Granulación/patología , Humanos , Cicatrización de Heridas/fisiología , Periodontitis/patología , Periodontitis/cirugía , Periodoncio/patología , Regeneración/fisiologíaRESUMEN
BACKGROUND: Numerous studies have proposed that periodontitis is a potential risk factor for Alzheimer's disease. However, the association between periodontitis and brain normal cognition in aged and elderly individuals (NCs) is unclear. Such a link could provide clues to Alzheimer's disease development and strategies for early prevention. OBJECTIVE: To explore the associations between periodontal condition and metrics of both brain structure and function among NCs with the help of multimodal magnetic resonance imaging (MRI). METHODS: High-resolution T1-weighted structural data, resting-state functional-MRI data, and measures of periodontal condition were collected from 40 NCs. Cortical volume, thickness, and area as well as regional homogeneity were calculated with the aid of DPABISurf software. Correlation analyses were then conducted between each imaging metric and periodontal index. RESULTS: Consistent negative correlations were observed between severity of periodontitis (mild, moderate, severe) and cortical volume, area, and thickness, not only in brain regions that took charge of primary function but also in brain regions associated with advanced cognition behavior. Among participants with mild attachment loss (AL) and a shallow periodontal pocket depth (PPD), periodontal index was positively correlated with most measures of brain structure and function, while among participants with severe AL and deep PPD, periodontal index was negatively correlated with measures of brain structure and function (all p < .005 for each hemisphere). CONCLUSIONS: Our results demonstrate that periodontitis is associated with widespread changes in brain structure and function among middle-aged and elderly adults without signs of cognitive decline, which might be a potential risk factor for brain damage.
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Enfermedad de Alzheimer , Enfermedades Periodontales , Periodontitis , Anciano , Adulto , Persona de Mediana Edad , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Periodontitis/complicaciones , Periodontitis/diagnóstico por imagen , Periodontitis/patología , Cognición , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades Periodontales/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: The biological effects of atmospheric plasma (cold plasma) show its applicability for controlling the etiological factors that involve tissue repair. Thus, the study evaluated the effect of atmospheric plasma therapy in the control of tissue inflammation and bone remodeling in experimental periodontitis. METHODS: Fifty-six rats were subjected to ligation in the cervical region of the first maxillary molars (8 weeks). The animals were divided into two groups (n = 28): periodontitis without treatment group (P group), and periodontitis with atmospheric plasma treatment group (P + AP group). Tissue samples were collected at 2 and 4 weeks after treatment to analyze the inflammation and bone remodeling by biochemical, histomorphometric, and immunohistochemical analyses. RESULTS: Inflammatory infiltration in the gingival and periodontal ligament was lower in the P + AP group than in the P group (p < .05). The MPO and NAG levels were higher in the P + AP group compared to P group (p < .05). At 4 weeks, the TNF-α level was lower and the IL-10 level was higher in the P + AP group compared to P group (p < .05). In the P + AP group, the IL-1ß level increased in the second week and decreased in the fourth week (p < .05), the number of blood vessels was high in the gingival and periodontal ligament in the second and fourth week (p < .05); and the number of fibroblasts in the gingival tissue was low in the fourth week, and higher in the periodontal tissue in both period (p < .05). Regarding bone remodeling, the RANK and RANKL levels decreased in the P + AP group (p < .05). The OPG level did not differ between the P and P + AP groups (p > .05), but decreased from the second to the fourth experimental week in P + AP group (p < .05). CONCLUSIONS: The treatment of experimental periodontitis with atmospheric plasma for 4 weeks modulated the inflammatory response to favor the repair process and decreased the bone resorption biomarkers, indicating a better control of bone remodeling in periodontal disease.
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Remodelación Ósea , Periodontitis , Gases em Plasma , Animales , Periodontitis/terapia , Periodontitis/patología , Periodontitis/sangre , Gases em Plasma/uso terapéutico , Ratas , Masculino , Modelos Animales de Enfermedad , Inflamación , Encía/patología , Ligamento Periodontal/patología , Interleucina-1beta/sangre , Interleucina-1beta/análisis , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/análisis , Interleucina-10/sangre , Interleucina-10/análisis , Ligando RANK/análisis , Ligando RANK/sangre , Ratas Wistar , Osteoprotegerina/análisis , Osteoprotegerina/sangreRESUMEN
BACKGROUND: Periodontitis is a chronic inflammatory disease defined by the pathologic loss of the periodontal ligament and alveolar bone in relation to aging. Although clinical cohort studies reported that periodontitis is significantly elevated in males compared to females, emerging evidence indicates that females with dementia are at a greater risk for periodontitis and decreased alveolar bone. OBJECTIVE: This study aimed to evaluate whether dementia is a potential sex-dependent risk factor for periodontal bone loss using an experimental model of periodontitis induced in the triple transgenic (3x-Tg) dementia-like mice and clinical samples collected from senior 65 plus age patients with diagnosed dementia. MATERIALS AND METHODS: We induced periodontitis in dementia-like triple-transgenic (3x-Tg) male and female mice and age-matched wild-type (WT) control mice by ligature placement. Then, alveolar bone loss and osteoclast activity were evaluated using micro-CT and in situ imaging assays. In addition, we performed dental examinations on patients with diagnosed dementia. Finally, dementia-associated Aß42 and p-Tau (T181) and osteoclastogenic receptor activator of nuclear factor kappa-Β ligand (RANKL) in gingival crevicular fluid (GCF) collected from mice and clinical samples were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Alveolar bone loss and in situ osteoclast activity were significantly elevated in periodontal lesions of 3x-Tg females but not males, compared to wild-type control mice. In addition, we also observed that the probing pocket depth (PPD) was also significantly elevated in female patients with dementia. Using ELISA assay, we observed that females had elevated levels of osteoclastogenic RANKL and dementia-associated Aß42 and p-Tau (T181) in the GCF collected from experimental periodontitis lesions and clinical samples. CONCLUSION: Altogether, we demonstrate that females with dementia have an increased risk for periodontal bone loss compared to males.
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Pérdida de Hueso Alveolar , Demencia , Modelos Animales de Enfermedad , Ratones Transgénicos , Periodontitis , Ligando RANK , Animales , Femenino , Pérdida de Hueso Alveolar/patología , Pérdida de Hueso Alveolar/diagnóstico por imagen , Pérdida de Hueso Alveolar/metabolismo , Masculino , Ratones , Demencia/etiología , Humanos , Anciano , Ligando RANK/análisis , Ligando RANK/metabolismo , Factores Sexuales , Periodontitis/complicaciones , Periodontitis/patología , Microtomografía por Rayos X , Osteoclastos/patología , Péptidos beta-Amiloides/metabolismo , Líquido del Surco Gingival/química , Fragmentos de Péptidos/análisis , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVE: Clinical studies found high levels of hepatocyte growth factor (HGF) expression in patients with periodontitis. Studies suggest that HGF plays an important role in periodontitis, is involved in inflammation, and modulates alveolar bone integrity in periodontitis. This study aims to investigate the effects and mechanisms of HGF in the progression of experimental periodontitis. METHODS: We used silk thread ligation to induce periodontitis in HGF-overexpressing transgenic (HGF-Tg) and wild-type C57BL/6J mice. The effects of HGF overexpression on alveolar bone destruction were assessed by microcomputed tomography imaging at baseline and on days 7, 14, 21, and 28. We analyzed the cytokines (IL-6 and TNF-α) and lymphocytes in periodontitis tissues by enzyme-linked immunosorbent assay and flow cytometry. The effects of HGF on alveolar bone destruction were further tested by quantifying the systemic bone metabolism markers CTXI and PINP and by RNA sequencing for the signaling pathways involved in bone destruction. Western blotting and immunohistochemistry were performed to further elucidate the involved signaling pathways. RESULTS: We found that experimental periodontitis increased HGF production in periodontitis tissues; however, the effects of HGF overexpression were inconsistent with disease progression. In the early stage of periodontitis, periodontal inflammation and alveolar bone destruction were significantly lower in HGF-Tg mice than in wild-type mice. In the late stage, HGF-Tg mice showed higher inflammatory responses and progressively aggravated bone destruction with continued stimulation of inflammation. We identified the IL-17/RANKL/TRAF6 pathway as a signaling pathway involved in the HGF effects on the progression of periodontitis. CONCLUSION: HGF plays divergent effects in the progression of experimental periodontitis and accelerates osteoclastic activity and bone destruction in the late stage of inflammation.
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Pérdida de Hueso Alveolar , Factor de Crecimiento de Hepatocito , Ratones Endogámicos C57BL , Ratones Transgénicos , Periodontitis , Microtomografía por Rayos X , Animales , Factor de Crecimiento de Hepatocito/metabolismo , Periodontitis/metabolismo , Periodontitis/patología , Ratones , Pérdida de Hueso Alveolar/metabolismo , Pérdida de Hueso Alveolar/diagnóstico por imagen , Pérdida de Hueso Alveolar/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Masculino , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Porphyromonas gingivalis is commonly known as one of the major pathogens contributing to periodontitis, and its persistent infection may increase the risk for the disease. The proinflammatory mediators, including IL-6, TNF-α, and cyclooxygenase-2 (COX-2)/PGE2, are closely associated with progression of periodontitis. In this study, we focused on the cysteine protease "gingipains," lysine-specific gingipain, arginine-specific gingipain (Rgp) A, and RgpB, produced by P. gingivalis, and used the wild-type strain and several gene-deletion mutants (rgpA, rgpB, kgp, and fimA) to elucidate the involvement of gingipains in COX-2 expression and PGE2 production. We infected human monocytes, which are THP-1 cells and primary monocytes, with these bacterial strains and found that gingipains were involved in induction of COX-2 expression and PGE2 production. We have shown that the protease activity of gingipains was crucial for these events by using gingipain inhibitors. Furthermore, activation of ERK1/2 and IκB kinase was required for gingipain-induced COX-2 expression/PGE2 production, and these kinases activated two transcription factors, c-Jun/c-Fos (AP-1) and NF-κB p65, respectively. In particular, these data suggest that gingipain-induced c-Fos expression via ERK is essential for AP-1 formation with c-Jun, and activation of AP-1 and NF-κB p65 plays a central role in COX-2 expression/PGE2 production. Thus, we show the (to our knowledge) novel finding that gingipains with the protease activity from P. gingivalis induce COX-2 expression and PGE2 production via activation of MEK/ERK/AP-1 and IκB kinase/NF-κB p65 in human monocytes. Hence it is likely that gingipains closely contribute to the inflammation of periodontal tissues.
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Ciclooxigenasa 2/biosíntesis , Dinoprostona/biosíntesis , Cisteína-Endopeptidasas Gingipaínas/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Periodontitis/patología , Porphyromonas gingivalis/metabolismo , Proteínas Bacterianas/genética , Línea Celular , Cisteína Endopeptidasas/genética , Proteínas Fimbrias/genética , Cisteína-Endopeptidasas Gingipaínas/genética , Humanos , Quinasa I-kappa B/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Monocitos/microbiología , Periodontitis/microbiología , Células THP-1 , Factor de Transcripción AP-1/metabolismo , Factor de Transcripción ReIA/metabolismoRESUMEN
BACKGROUND: MicroRNAs are differentially expressed in periodontitis tissues. They are involved in cellular responses to inflammation and can be used as markers for diagnosing periodontitis. Microarray analysis showed that the expression level of microRNA-671-5p in periodontal tissues of patients with periodontitis was increased. In this study, we investigated the mechanism of action of microRNA-671-5p in human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. METHODS AND RESULTS: HPDLSCs were treated with lipopolysaccharide (LPS) to establish an inflammation model. The cell survival rate was determined using the cell counting kit-8 (CCK8). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses were used to detect the expression of microRNA-671-5p and dual-specificity phosphatase (DUSP) 8 proteins, respectively, Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were detected using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter system was employed to determine the relationship between micoRNA-671-5p and DUSP8 expression. Activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway was confirmed using western blot analysis. Following the treatment of hPDLSCs with LPS, the expression levels of microRNA-671-5p in hPDLSCs were increased, cell viability decreased, and the expression of inflammatory factors displayed an increasing trend. MicroRNA-671-5p targets and binds to DUSP8. Silencing microRNA-671-5p or overexpressing DUSP8 can improve cell survival rate and reduce inflammatory responses. When DUSP8 was overexpressed, the expression of p-p38 was reduced. CONCLUSIONS: microRNA-671-5p targets DUSP8/p38 MAPK pathway to regulate LPS-induced proliferation and inflammation in hPDLSCs.
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Fosfatasas de Especificidad Dual , Inflamación , Lipopolisacáridos , MicroARNs , Ligamento Periodontal , Células Madre , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Supervivencia Celular/genética , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Lipopolisacáridos/farmacología , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citología , Periodontitis/genética , Periodontitis/metabolismo , Periodontitis/patología , Transducción de Señal/genética , Células Madre/metabolismoRESUMEN
AIM: To reveal the cellular composition and molecular environment of the periodontal and peri-implant inflammatory infiltrates through a single-cell sequencing technique, which may explain the pathological difference between these two diseases. A special focus was placed on the phenotypes and potential roles of neutrophils and fibroblasts in peri-implant/periodontal tissue immunity. MATERIALS AND METHODS: High-throughput single-cell transcriptomic profiling of peri-implant tissues from patients with peri-implantitis as well as periodontal tissues from patients with periodontitis and healthy donors was performed. Immunofluorescence analysis was carried out to further validate the identified cell subtypes and their involvement in peri-implantitis and periodontitis. RESULTS: Based on our single-cell resolution analysis, a quantified proportional increase of neutrophil (Neu) subtypes was shown in peri-implantitis. Among these, a predominance of Neutro_CXCR2 was revealed. We also found the involvement of inflammation-promoting fibroblasts as well as a predominance of CXCL8+ fibroblast-CXCR2+ neutrophil interaction in peri-implantitis. CONCLUSIONS: Our study indicated that the predominance of CXCL8+ fibroblast-CXCR2+ neutrophil interaction might underline the enhanced host response in peri-implantitis compared with periodontitis. This information offers a molecular basis by which fibroblast and neutrophil subtypes might be diagnostically and therapeutically targeted in peri-implantitis.
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Implantes Dentales , Periimplantitis , Periodontitis , Humanos , Neutrófilos , Inflamación , Periodontitis/patología , FibroblastosRESUMEN
AIM: To investigate the bidirectional influence between periodontitis and psoriasis, using the respective experimental models of ligature- and imiquimod-induced diseases on murine models. MATERIALS AND METHODS: Thirty-two C57/BL6J mice were randomly allocated to four experimental groups: control (P- Pso-), ligature-induced periodontitis (P+ Pso-), imiquimod-induced psoriasis (P- Pso+) and periodontitis and psoriasis (P+ Pso+). Samples (maxilla, dorsal skin and blood) were harvested immediately after death. Measures of periodontitis (distance between the cemento-enamel junction and alveolar bone crest [CEJ-ABC] and the number of osteoclasts) and psoriasis (epidermal thickness and infiltrate cell [/0.03mm2]) severity as well as systemic inflammation (IL-6, IL-17A, TNF-α) were collected. RESULTS: The P+ Pso+ group exhibited the most severe experimental periodontitis and psoriasis, with the highest values of CEJ-ABC, number of osteoclasts, epidermal thickness and infiltrate cells in the dorsal skin, as well as the highest blood cytokine concentration. The P+ Pso- group presented with higher cell infiltrate (/0.03mm2) compared to the control group (p <.05), while the P- Pso+ group showed substantially higher alveolar bone loss (CEJ-ABC) than the control group (p <.05). CONCLUSIONS: Experimental periodontitis may initiate and maintain psoriasiform skin inflammation and, vice versa, experimental psoriasis may contribute to the onset of periodontitis. In a combined model of the diseases, we propose a bidirectional association between periodontitis and psoriasis via systemic inflammation.
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Modelos Animales de Enfermedad , Imiquimod , Ratones Endogámicos C57BL , Periodontitis , Psoriasis , Animales , Psoriasis/complicaciones , Psoriasis/patología , Periodontitis/complicaciones , Periodontitis/patología , Ratones , Distribución Aleatoria , Masculino , Factor de Necrosis Tumoral alfa/sangre , Interleucina-17/sangre , Pérdida de Hueso Alveolar/patología , Pérdida de Hueso Alveolar/etiología , Osteoclastos/patologíaRESUMEN
INTRODUCTION: We examined the association of clinical, microbiological, and host response features of periodontitis with MRI markers of atrophy/cerebrovascular disease in the Washington Heights Inwood Columbia Aging Project (WHICAP) Ancillary Study of Oral Health. METHODS: We analyzed 468 participants with clinical periodontal data, microbial plaque and serum samples, and brain MRIs. We tested the association of periodontitis features with MRI features, after adjusting for multiple risk factors for Alzheimer's disease/Alzheimer's disease-related dementia (AD/ADRD). RESULTS: In fully adjusted models, having more teeth was associated with lower odds for infarcts, lower white matter hyperintensity (WMH) volume, higher entorhinal cortex volume, and higher cortical thickness. Higher extent of periodontitis was associated with lower entorhinal cortex volume and lower cortical thickness. Differential associations emerged between colonization by specific bacteria/serum antibacterial IgG responses and MRI outcomes. DISCUSSION: In an elderly cohort, clinical, microbiological, and serological features of periodontitis were associated with MRI findings related to ADRD risk. Further investigation of causal associations is warranted.
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Enfermedad de Alzheimer , Envejecimiento Cognitivo , Periodontitis , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética , Periodontitis/diagnóstico por imagen , Periodontitis/patologíaRESUMEN
Extracellular matrix metalloproteinase inducer (EMMPRIN) plays critical roles in the regulation of inflammation and bone metabolism. The roles of EMMPRIN signaling in osteoclasts are worthy of deep study. The present study aimed to investigate bone resorption in periodontitis through the intervention of EMMPRIN signaling. The distribution of EMMPRIN in human periodontitis was observed. RANKL-induced osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) were treated with EMMPRIN inhibitor in vitro. Rats with ligation-induced periodontitis were treated with EMMPRIN inhibitor and harvested for microcomputed tomography scanning, histologic observation, immunohistochemistry, and double immunofluorescence analysis. Positive expressions of EMMPRIN could be found in the CD68+-infiltrating cells. Downregulated EMMPRIN restrained osteoclast differentiation of BMMs in vitro, which also inhibited MMP-9 expression (*P < 0.05). In vivo, EMMPRIN inhibitor restrained ligation-induced bone resorption by decreasing tartrate-resistant acid phosphatase-positive osteoclasts. Both EMMPRIN-positive and MMP-9-positive osteoclasts were less common in the EMMPRIN inhibitor groups than in the control groups. Intervention of EMMPRIN signaling in osteoclasts could probably provide a potential therapeutic target for attenuating ligation-induced bone resorption.
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Resorción Ósea , Periodontitis , Ratones , Ratas , Humanos , Animales , Osteoclastos , Basigina/análisis , Basigina/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Microtomografía por Rayos X , Resorción Ósea/patología , Periodontitis/patología , Ligando RANK , Diferenciación CelularRESUMEN
Periodontitis, a prevalent inflammatory condition, affects the supporting structures of teeth, leading to significant oral health challenges. Traditional treatments have primarily focused on mechanical debridement, antimicrobial therapy, and surgery, which often fail to restore lost periodontal structures. Emerging as a novel approach in regenerative medicine, extracellular vesicle (EV) therapy, including exosomes, leverages nano-sized vesicles known for facilitating intercellular communication and modulating physiological and pathological processes. This study is a proof-of-concept type that evaluates the clinical efficacy of EV therapy as a non-surgical treatment for stage I-III periodontitis, focusing on its anti-inflammatory and regenerative potential. The research involved seven patients undergoing the therapy, and seven healthy individuals. Clinical parameters, including the plaque index, bleeding on probing, probing depth, and attachment level, were assessed alongside cytokine levels in the gingival crevicular fluid. The study found significant improvements in clinical parameters, and a marked reduction in pro-inflammatory cytokines post-treatment, matching the levels of healthy subjects, underscoring the therapy's ability to not only attenuate inflammation and enhance tissue regeneration, but also highlighting its potential in restoring periodontal health. This investigation illuminates the promising role of EV therapy in periodontal treatment, advocating for a shift towards therapies that halt disease progression and promote structural and functional restoration of periodontal tissues.
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Vesículas Extracelulares , Líquido del Surco Gingival , Inflamación , Periodontitis , Regeneración , Humanos , Vesículas Extracelulares/metabolismo , Femenino , Periodontitis/terapia , Periodontitis/metabolismo , Periodontitis/patología , Masculino , Adulto , Persona de Mediana Edad , Inflamación/terapia , Inflamación/metabolismo , Inflamación/patología , Líquido del Surco Gingival/metabolismo , Citocinas/metabolismo , Resultado del TratamientoRESUMEN
Porphyromonas gingivalis (Pg) and its gingipain proteases contribute to Alzheimer's disease (AD) pathogenesis through yet unclear mechanisms. Cellular secretion of small extracellular vesicles or exosomes (EXO) increases with aging as part of the senescence-associated secretory phenotype (SASP). We have shown that EXO isolated from Pg-infected dendritic cells contain gingipains and other Pg antigens and transmit senescence to bystander gingival cells, inducing alveolar bone loss in mice in vivo. Here, EXO were isolated from the gingiva of mice and humans with/without periodontitis (PD) to determine their ability to penetrate the blood-brain barrier (BBB) in vitro and in vivo. PD was induced by Pg oral gavage for 6 weeks in C57B6 mice. EXO isolated from the gingiva or brain of donor Pg-infected (PD EXO) or control animals (Con EXO) were characterized by NTA, Western blot, and TEM. Gingival PD EXO or Con EXO were labeled and injected into the gingiva of uninfected WT mouse model. EXO biodistribution in brains was tracked by an in vivo imaging system (IVIS) and confocal microscopy. The effect of human PD EXO on BBB integrity and permeability was examined using TEER and FITC dextran assays in a human in vitro 3D model of the BBB. Pg antigens (RGP and Mfa-1) were detected in EXO derived from gingival and brain tissues of donor Pg-infected mice. Orally injected PD EXO from donor mice penetrated the brains of recipient uninfected mice and colocalized with hippocampal microglial cells. IL-1ß and IL-6 were expressed in human PD EXO and not in Con EXO. Human PD EXO promoted BBB permeability and penetrated the BBB in vitro. This is the first demonstration that microbial-induced EXO in the oral cavity can disseminate, cross the BBB, and may contribute to AD pathogenesis.
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Barrera Hematoencefálica , Vesículas Extracelulares , Encía , Periodontitis , Porphyromonas gingivalis , Barrera Hematoencefálica/metabolismo , Animales , Humanos , Ratones , Vesículas Extracelulares/metabolismo , Porphyromonas gingivalis/metabolismo , Porphyromonas gingivalis/patogenicidad , Periodontitis/microbiología , Periodontitis/metabolismo , Periodontitis/patología , Encía/metabolismo , Encía/microbiología , Ratones Endogámicos C57BL , Masculino , Exosomas/metabolismo , Femenino , Infecciones por Bacteroidaceae/microbiología , Infecciones por Bacteroidaceae/metabolismoRESUMEN
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.