Salivary ACE2 and TMPRSS2 link to periodontal status and metabolic parameters

Zhao, Dan; Cheng, Tianfan; Koohi‐Moghadam, Mohamad; Wu, Mei‐Zhen; Yu, Shuk Yin; Ding, Xiaobin; Pelekos, George; Yiu, Kai Hang; Jin, Lijian

doi:10.1002/ctd2.37

Cited by 5 publications

(4 citation statements)

References 112 publications

(251 reference statements)

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“…This disparity may be related to differences between E. c. and P. g. LPS, as as differences between pulmonary endothelial cells and PD-CD4 + T cells. Consistent with our findings, saliva ACE2 increased and serum ACE2 decreased in periodontal disease, 43 and there is an inverse correlation between ACE2 and miR-1246. 44 In addition to ACE2, EV-miR-1246 has various target genes, such as the nuclear factor of activated T cells 5 (NFAT5) in MSCs from inflamed periodontium 24 and glycogen synthase kinase 3 beta in human umbilical cord blood MSCs from hepatic tissues damaged by ischemia/reperfusion.…”

Section: Discussionsupporting

confidence: 91%

Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246

Xia,

Cheng,

Zhang

et al. 2023

The FASEB Journal

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T‐cell‐mediated immunity is crucial in the immunopathology of periodontitis. The restoration of the homeostasis between the T helper cell 17 (Th17) and regulatory T cell (Treg) subsets by extracellular vesicles (EVs) obtained from human bone marrow stem cells (hBMSCs) promotes new bone formation and suppresses inflammation. Uncovering the functions of hBMSC‐derived EVs in the immune microenvironment of periodontal tissue and their underlying regulatory mechanisms may shed new light on developing potential cell‐free immunotherapies for periodontal regeneration. Here, we reported that the Th17/Treg ratio elevated in peripheral blood from periodontitis patients. Furthermore, we found that hBMSC‐derived EVs could reduce the Th17/Treg ratio in CD4+ T cells from periodontitis patients in vitro and ameliorate conditions of experimental periodontitis in mice. Additionally, by investigating the differentially expressed miRNAs and target genes in EVs from hBMSCs stimulated with Porphyromonas gingivalis LPS using miRNA sequencing, we found that EV‐miR‐1246 is highly effective at downregulating the ratio of Th17/Treg in vitro. Mechanistically, EV‐miR‐1246 suppressed expression of its potential target angiotensin‐converting enzyme 2 (ACE2) and increased the p‐Yes‐associated protein (YAP)1/YAP1 ratio in CD4+ T cells. Our results indicated that hBMSC‐derived EVs improve periodontitis via miR‐1246, consequently downregulating Th17/Treg ratio, and represented a promising therapeutic target for precision treatment in periodontitis.

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Section: Discussionsupporting

confidence: 91%

Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246

Xia,

Cheng,

Zhang

et al. 2023

The FASEB Journal

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“…Through bioinformatics analysis and dual luciferase assays, we identi ed ACE2 as the target gene of hBMSC-derived exosomal miR-1246 in CD4 + T cells. The level of soluble ACE2 in saliva was positively correlated with the severity of periodontitis in a recent clinical study 39 . Furthermore, exosomes containing miR-1246 inhibitor reduced the expression of ACE2 in Escherichia coli LPS (E.c.…”

Section: Discussionmentioning

confidence: 84%

“…Consistent with our ndings, inhibition of miR-1246 increased ACE2 expression in small airway epithelium of smokers 41 . In addition to ACE2, exosomal miR-1246 has various target genes, such as nuclear factor of activated T cells 5 of mesenchymal stem cells in in amed periodontium 24 and glycogen synthase kinase 3 beta of human umbilical cord blood mesenchymal stem cells in hepatic ischemia/reperfusion injury 38,39 . However, further studies are needed to characterize other possible target genes regarding exosomal miR-1246.…”

Section: Discussionmentioning

confidence: 99%

hBMSC-derived Exosomes Mitigate Th17/Treg Homeostasis in Periodontitis via miR-1246

Xia

Cheng

Zhou

et al. 2022

Preprint

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Background Chronic inflammatory bone loss in periodontitis is closely related to helper T cell 17 (Th17) / regulatory T cell (Treg) imbalance. The therapeutic function of mesenchymal stem cells is mainly attributed to the paracrine exosomes. We aimed to investigate the immunomodulatory effect of human bone marrow mesenchymal stem cells (hBMSC)-derived exosomes in Th17/Treg homeostasis in periodontitis. Methods Peripheral blood was collected from periodontitis patients or healthy donors. The level of Th17-related biomarker interleukin-17A (IL-17A) and Treg-related forkhead box protein 3 (FOXP3) was analyzed by ELISA, and mRNA expression level of RAR-related orphan receptor C (RORC) and FOXP3 was detected by qRT-PCR. Naïve CD4+ T cells extracted from the peripheral blood of periodontitis patients were co-cultured with hBMSC-derived exosomes from healthy subjects. The ratio of Th17/Treg was examined by flow cytometry and the expression of inflammatory cytokines was determined by qRT-PCR. In vivo, exosomes-loaded hydrogel was injected into periodontal pockets of mice with experimental periodontitis. The periodontal inflammation and bone regeneration was evaluated by histological staining, immunofluorescence staining and micro-CT. Furthermore, the differentially expressed miRNAs in exosomes stimulated by P.g. LPS were investigated by miRNA sequencing and bioinformatics analysis. The interaction between candidate miRNA and its target gene in CD4+ T cells was verified by dual luciferase activity assay. Lastly, the downstream Yes-related protein 1(YAP1)/Hippo pathway was evaluated by western blotting. Results The ratio of Th17/Treg is significantly increased in the peripheral blood of periodontitis patients. hBMSC-derived exosomes decreased Th17/Treg ratio in CD4+ T cells in vitro and ameliorated inflammation and bone loss in periodontitis mice. Mechanistically, the enrichment of miR-1246 in exosomes showed the enhanced effects of down-regulating Th17/Treg ratio, which could be reversed by miR-1246 inhibitor. Furthermore, exosomal miR-1246 suppressed the expression of the target protein angiotensin converting enzyme2 (ACE2) and upregulated the expression ratio P-YAP1/YAP1 in CD4+ T cells. Conclusions hBMSC-derived exosomes could alleviate periodontal inflammation through modulating the balance of Th17/Treg via targeting ACE2 and downregulating YAP1/Hippo signaling pathway, which shed light on a novel cell-free immunotherapy for periodontal regeneration.

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“…According to a recent systematic review, aMMP-8/MMP-8 is currently the most accurate diagnostic biomarker in gingival crevicular fluid and saliva for periodontitis in systemically healthy patients [82][83][84]. In consideration of the above mentioned pathophysiological information related to COVID-19 entry into the body via the ACE2 receptors in the oral mucosa, it is of note that salivary levels of ACE2 increase with the severity and complexity of periodontitis and correlate positively with alveolar bone loss and salivary MMP8 [85].…”

Section: Diagnostic Aspectsmentioning

confidence: 99%

The Oral-Systemic Link: A Review about the strong Correlation between Diabetes mellitus, Periodontits and COVID-19 Outcome

Pfützner

Schaedlich

Möller

et al. 2023

MRAJ

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The SARS-CoV-2 virus leads to symptoms ranging from mild flu symptoms to severe COVID-19 pneumonia requiring mechanical ventilation and even death. According to epidemiological observations, diabetes mellitus is a major risk factor for severe outcome, next to older age, s, hypertension, and other serious chronic illnesses. Recent studies have determined that the oral cavity mucosa is the main entry portal for the SARS-CoV-2 virus into the body. The viruses accumulate in the mouth at locations where the main viral receptor is highly expressed. The oral pathway of the virus into the body and the contributing factors are described in this review. The immune system of people with diabetes is generally impaired. Diabetes induces chronic systemic inflammation, which regularly manifests as periodontitis in the oral cavity. Furthermore, frequent hyperglycemia leads to additional weakening of the mucosal immune barrier. These findings provide plausible explanations for the more frequent severe courses of respiratory viral infections in diabetes patients. An oral examination helps to identify patients at elevated risk. Activated matrix metalloproteinase-8 (aMMP-8) is an established biomarker for measuring the degree of oral inflammation and is an indicator of the destruction of collagen and bone structures in the mouth. aMMP-8 point-of-care tests are readily available. We propose that the current recommendations for the prevention of SARS-CoV-2-associated severe COVID-19 disease should be extended to consider the aspects of measuring and sanitizing oral health, as well as to include preventive regular daily disinfection of the mouth and the pharynx.

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Salivary ACE2 and TMPRSS2 link to periodontal status and metabolic parameters

Cited by 5 publications

References 112 publications

Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246

Human bone marrow mesenchymal stem cell‐derived extracellular vesicles restore Th17/Treg homeostasis in periodontitis via miR‐1246

hBMSC-derived Exosomes Mitigate Th17/Treg Homeostasis in Periodontitis via miR-1246

The Oral-Systemic Link: A Review about the strong Correlation between Diabetes mellitus, Periodontits and COVID-19 Outcome

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