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Banjara S, Berggreen E, Igland J, Åstrøm AK, Midttun Ø, Bunæs D, Sulo G. Plasma levels of immune system activation markers Neopterin and Kynurenine-to-Tryptophan Ratio, and oral health among community-dwelling adults in Norway: a population-based, cohort study. Acta Odontol Scand 2025; 84:218-225. [PMID: 40356307 PMCID: PMC12095943 DOI: 10.2340/aos.v84.43535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 03/31/2025] [Indexed: 05/15/2025]
Abstract
OBJECTIVE Periodontitis is a condition characterised by inflammation. Neopterin and kynurenine-to-tryptophan ratio (KTR) are markers of immune system activation in response to inflammation whose elevated levels are linked to higher incidence and poorer prognosis of various systemic diseases. Their potential association with oral health remains underexplored. The aim of this study was to prospectively investigate the associations between these biomarkers and periodontal health status among community-dwelling adults in Hordaland County, Norway. MATERIALS AND METHODS Neopterin and KTR were measured in 1,298 participants of the Hordaland Health Study, 1997-1999. Information on oral health indicators was obtained from the 'Hordaland-Oral Health Survey', 2020-2022. Ordinal logistic regression and negative binomial regression were used to explore the association between biomarkers and periodontitis, tooth loss, and current inflammation (extend of sites with pocket depth ≥4mm and bleeding on probing) and odds ratios (OR) and incidence rate ratios (IRR), along with respective 95% confidence intervals (CI) were reported. RESULTS No association was found between biomarker levels and periodontitis [neopterin: OR = 0.96, 95% CI: 0.69-1.33 for fourth (Q4) vs. first quartile (Q1); KTR: OR = 0.85, 95% CI: 0.61-1.18 for Q4 vs. Q1], tooth loss [neopterin: IRR = 1.00, 95% CI: 0.94-1.06 for Q4 vs. Q1; KTR: IRR = 0.97, 95% CI: 0.91-1.03 for Q4 vs. Q1) or extend of inflammation [neopterin: OR = 0.87, 95% CI: 0.70-1.09 for Q4 vs. Q1; KTR: OR = 0.98, 95% CI: 0.78-1.23 for Q4 vs. Q1]. CONCLUSION Plasma levels of neopterin and KTR were not prospectively associated with periodontal health and number of missing teeth.
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Affiliation(s)
- Sarala Banjara
- Oral Health Centre of Expertise in Western Norway, Bergen, Norway
| | - Ellen Berggreen
- Oral Health Centre of Expertise in Western Norway, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Jannicke Igland
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | | | | | - Dagmar Bunæs
- Department of Clinical Odontology, University of Bergen, Bergen, Norway
| | - Gerhard Sulo
- Oral Health Centre of Expertise in Western Norway, Bergen, Norway; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
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Kis-György R, Körtési T, Anicka A, Nagy-Grócz G. The Connection Between the Oral Microbiota and the Kynurenine Pathway: Insights into Oral and Certain Systemic Disorders. Curr Issues Mol Biol 2024; 46:12641-12657. [PMID: 39590344 PMCID: PMC11593024 DOI: 10.3390/cimb46110750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
The oral microbiome, comprising bacteria, fungi, viruses, and protozoa, is essential for maintaining both oral and systemic health. This complex ecosystem includes over 700 bacterial species, such as Streptococcus mutans, which contributes to dental caries through acid production that demineralizes tooth enamel. Fungi like Candida and pathogens such as Porphyromonas gingivalis are also significant, as they can lead to periodontal diseases through inflammation and destruction of tooth-supporting structures. Dysbiosis, or microbial imbalance, is a key factor in the development of these oral diseases. Understanding the composition and functions of the oral microbiome is vital for creating targeted therapies for these conditions. Additionally, the kynurenine pathway, which processes the amino acid tryptophan, plays a crucial role in immune regulation, neuroprotection, and inflammation. Oral bacteria can metabolize tryptophan, influencing the production of kynurenine, kynurenic acid, and quinolinic acid, thereby affecting the kynurenine system. The balance of microbial species in the oral cavity can impact tryptophan levels and its metabolites. This narrative review aims to explore the relationship between the oral microbiome, oral diseases, and the kynurenine system in relation to certain systemic diseases.
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Affiliation(s)
- Rita Kis-György
- Section of Health Behaviour and Health Promotion, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31., H-6726 Szeged, Hungary;
- Doctoral School of Interdisciplinary Medicine, University of Szeged, Szőkefalvi–Nagy Béla u. 4/B, H-6720 Szeged, Hungary
| | - Tamás Körtési
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31., H-6726 Szeged, Hungary;
- Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged, H-6720 Szeged, Hungary
- HUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, Danube Neuroscience Research Laboratory, University of Szeged (HUN-REN-SZTE), Tisza Lajos krt. 113, H-6725 Szeged, Hungary
| | - Alexandra Anicka
- Department of Obstetrics and Gynecology, Semmelweis University, Üllői Út 78/A, H-1182 Budapest, Hungary;
| | - Gábor Nagy-Grócz
- Department of Theoretical Health Sciences and Health Management, Faculty of Health Sciences and Social Studies, University of Szeged, Temesvári krt. 31., H-6726 Szeged, Hungary;
- Preventive Health Sciences Research Group, Incubation Competence Centre of the Centre of Excellence for Interdisciplinary Research, Development and Innovation of the University of Szeged, H-6720 Szeged, Hungary
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Önder C, Akdoğan N, Kurgan Ş, Balci N, Serdar CC, Serdar MA, Günhan M. Does smoking influence tryptophan metabolism in periodontal inflammation? A cross-sectional study. J Periodontal Res 2023; 58:1041-1051. [PMID: 37526075 DOI: 10.1111/jre.13166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/11/2023] [Accepted: 07/20/2023] [Indexed: 08/02/2023]
Abstract
OBJECTIVES The aim of this study was to identify the effects of smoking and periodontal inflammation on tryptophan-kynurenine metabolism as well as the correlation between these findings and clinical periodontal parameters. BACKGROUND It has been shown that the tryptophan amino acid's primary catabolic pathway, the kynurenine pathway (KP), may serve as a key biomarker for periodontal disease. Although there are studies investigating the effect of smoking on KYN-TRP metabolism, the effect of smoking on periodontal disease through KP has not been revealed so far. METHODS The salivary and serum samples were gathered from 24 nonsmoker (NS-P) stage III, grade B generalized periodontitis and 22 smoker (S-P) stage III, grade C generalized periodontitis patients, in addition to 24 nonsmoker (NS-C) and 24 smoker (S-C) periodontally healthy control individuals. Saliva and serum IL-6, kynurenine (KYN), and tryptophan (TRP) values, and KYN/TRP ratio were analyzed by liquid chromatography-mass spectrometry. Clinical periodontal measurements were recorded. RESULTS Salivary TRP values were significantly higher in both periodontitis groups than control groups (p < .05). Salivary KYN values were highest in NS-P group (p < .05). Salivary KYN values did not differ significantly between periodontitis groups (p = .84). Salivary KYN/TRP ratio was significantly lower in NS-P group compared to other groups (p < .001). Serum TRP value is higher in S-P group than other groups; however, significant difference was found in S-C group (p < .05). Serum KYN values were significantly lower in smokers than nonsmokers. Serum KYN/TRP ratio is higher in NS-P group. NS-P group has the highest salivary IL-6 levels, NS-C group has the lowest values (p < .05). CONCLUSIONS Our results point out that smoking exacerbates inflammation in the periodontium and increases TRP destruction and decreases IDO activity by suppressing KP in serum. As a result, kynurenine and its metabolites may be significant biomarkers in the link between smoking and periodontal disease.
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Affiliation(s)
- Canan Önder
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey
| | - Nihan Akdoğan
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey
| | - Şivge Kurgan
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey
| | - Nur Balci
- Department of Periodontology, Faculty of Dentistry, Medipol University, İstanbul, Turkey
| | - Ceyhan Ceran Serdar
- Department of Medical Biology and Genetics, Faculty of Medicine, Ankara Medipol University, Ankara, Turkey
| | - Muhittin A Serdar
- Department of Medical Biochemistry, Faculty of Medicine, Acıbadem University, Ankara, Turkey
| | - Meral Günhan
- Department of Periodontology, Faculty of Dentistry, Ankara University, Ankara, Turkey
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Ang HP, Makpol S, Nasaruddin ML, Ahmad NS, Tan JK, Wan Zaidi WA, Embong H. Lipopolysaccharide-Induced Delirium-like Behaviour in a Rat Model of Chronic Cerebral Hypoperfusion Is Associated with Increased Indoleamine 2,3-Dioxygenase Expression and Endotoxin Tolerance. Int J Mol Sci 2023; 24:12248. [PMID: 37569622 PMCID: PMC10418785 DOI: 10.3390/ijms241512248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/17/2023] [Accepted: 07/18/2023] [Indexed: 08/13/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) and the tryptophan-kynurenine pathway (TRP-KP) are upregulated in ageing and could be implicated in the pathogenesis of delirium. This study evaluated the role of IDO/KP in lipopolysaccharide (LPS)-induced delirium in an animal model of chronic cerebral hypoperfusion (CCH), a proposed model for delirium. CCH was induced by a permanent bilateral common carotid artery ligation (BCCAL) in Sprague Dawley rats to trigger chronic neuroinflammation-induced neurodegeneration. Eight weeks after permanent BCCAL, the rats were treated with a single systemic LPS. The rats were divided into three groups: (1) post-BCCAL rats treated with intraperitoneal (i.p.) saline, (2) post-BCCAL rats treated with i.p. LPS 100 μg/kg, and (3) sham-operated rats treated with i.p. LPS 100 μg/kg. Each group consisted of 10 male rats. To elucidate the LPS-induced delirium-like behaviour, natural and learned behaviour changes were assessed by a buried food test (BFT), open field test (OFT), and Y-maze test at 0, 24-, 48-, and 72 h after LPS treatment. Serum was collected after each session of behavioural assessment. The rats were euthanised after the last serum collection, and the hippocampi and cerebral cortex were collected. The TRP-KP neuroactive metabolites were measured in both serum and brain tissues using ELISA. Our data show that LPS treatment in CCH rats was associated with acute, transient, and fluctuated deficits in natural and learned behaviour, consistent with features of delirium. These behaviour deficits were mild compared to the sham-operated rats, which exhibited robust behaviour impairments. Additionally, heightened hippocampal IDO expression in the LPS-treated CCH rats was associated with reduced serum KP activity together with a decrease in the hippocampal quinolinic acid (QA) expression compared to the sham-operated rats, suggested for the presence of endotoxin tolerance through the immunomodulatory activity of IDO in the brain. These data provide new insight into the underlying mechanisms of delirium, and future studies should further explore the role of IDO modulation and its therapeutic potential in delirium.
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Affiliation(s)
- Hui Phing Ang
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
| | - Suzana Makpol
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Muhammad Luqman Nasaruddin
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Nurul Saadah Ahmad
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
| | - Jen Kit Tan
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (M.L.N.); (J.K.T.)
| | - Wan Asyraf Wan Zaidi
- Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia;
| | - Hashim Embong
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia (N.S.A.)
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Behm C, Blufstein A, Gahn J, Moritz A, Rausch-Fan X, Andrukhov O. 25-hydroxyvitamin D 3 generates immunomodulatory plasticity in human periodontal ligament-derived mesenchymal stromal cells that is inflammatory context-dependent. Front Immunol 2023; 14:1100041. [PMID: 36761739 PMCID: PMC9902380 DOI: 10.3389/fimmu.2023.1100041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
INTRODUCTION Human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) exhibit a tight bi-directional interaction with CD4+ T lymphocytes. The hPDL-MSCs' immunomodulatory abilities are drastically enhanced by pro-inflammatory cytokines via boosting the expression of various immunomediators. 25-hydroxyvitamin D3 (25(OH)D3), the major metabolite of vitamin D3 in the blood, affects both hPDL-MSCs and CD4+ T lymphocytes, but its influence on their interaction is unknown. METHODS Therefore, primary hPDL-MSCs were stimulated in vitro with tumor necrosis factor (TNF)-α a or interleukin (IL)-1β in the absence and presence of 25(OH)D3 followed by an indirect co-culture with phytohemagglutinin-activated CD4+ T lymphocytes. The CD4+ T lymphocyte proliferation, viability, and cytokine secretion were analyzed. Additionally, the expression of various immunomediators in hPDL-MSCs was investigated, and their implication was verified by using pharmacological inhibitors. RESULTS 25(OH)D3 significantly counteracted the suppressive effects of IL-1β-treated hPDL-MSCs on CD4+ T lymphocyte proliferation, whereas no effects were observed in the presence of TNF-α. Additionally, 25(OH)D3 significantly increased the percentage of viable CD4+ T lymphocytes via TNF-α- or IL-1β-treated hPDL-MSCs. It also caused a significant decrease in interferon-γ, IL-17A, and transforming growth factor-β productions, which were triggered by TNF-α-treated hPDL-MSCs. 25(OH)D3 significantly decreased the production of various immunomediators in hPDL-MSCs. Inhibition of two of them, prostaglandin E2 and indoleamine-2,3-dioxygenase-1, partially abolished some of the hPDL-MSCs-mediated effects of 25(OH)D3 on CD4+ T lymphocytes. CONCLUSION These data indicate that 25(OH)D3 influences the immunomodulatory activities of hPDL-MSCs. This modulatory potential seems to have high plasticity depending on the local cytokine conditions and may be involved in regulating periodontal tissue inflammatory processes.
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Affiliation(s)
- Christian Behm
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Alice Blufstein
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Johannes Gahn
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Andreas Moritz
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Xiaohui Rausch-Fan
- Clinical Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
- Center for Clinical Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
| | - Oleh Andrukhov
- Competence Center Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
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Influence of periodontal inflammation on tryptophan-kynurenine metabolism: a cross-sectional study. Clin Oral Investig 2022; 26:5721-5732. [PMID: 35588020 DOI: 10.1007/s00784-022-04528-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/04/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVES Kynurenine pathway (KP) is the primary way of degrading tryptophan (TRP) and generates several bioactive metabolites (such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3OHKYN)) to regulate biological processes that include host-microbiome signaling and immune cell response. This study is aimed to determine the relationship between periodontal inflammation and tryptophan-kynurenine metabolism and identify their association with periodontal clinical parameters. MATERIALS AND METHODS Saliva and serum samples were collected from 20 stage III, grade B generalized periodontitis patients, and 20 periodontally healthy control individuals. Samples were analyzed for IL-6, KYN, TRP, KYN/TRP ratio, KYNA, 3OHKYN, picolinic acid (PA), and quinolinic acid (QA) by liquid chromatography-mass spectrometry. Clinical periodontal parameters (plaque index (PI), probing pocket depth (PPD), gingival recession (GR), clinical attachment loss (CAL), and bleeding on probing (BOP)) were recorded. RESULTS Clinical parameters were significantly higher in the periodontitis group (p < 0.001). Salivary IL-6, TRP, KYN, KYNA, PA, and QA levels were significantly higher and KYN/TRP ratio was significantly lower in periodontitis group than control group (p < 0.05). Serum KYN, KYN/TRP ratio and PA levels were significantly higher in periodontitis group than control group (p < 0.05). PPD, BOP, PI, and CAL had significantly positive correlations with salivary IL-6, TRP, PA, QA, and serum KYN and significantly negative correlations with salivary KYN/TRP ratio. CONCLUSIONS Our results suggest that periodontal inflammation plays a role in local and systemic tryptophan-kynurenine metabolism. CLINICAL RELEVANCE Due to their effects on the immune and inflammatory systems, kynurenines may be potential agents for diagnosis and treatment of periodontal diseases.
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Kyawsoewin M, Limraksasin P, Ngaokrajang U, Pavasant P, Osathanon T. Extracellular adenosine triphosphate induces IDO and IFNγ expression of human periodontal ligament cells through P 2 X 7 receptor signaling. J Periodontal Res 2022; 57:742-753. [PMID: 35510301 DOI: 10.1111/jre.12997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/31/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Mechanical stimuli induce the release of adenosine triphosphate into the extracellular environment by human periodontal ligament cells (hPDLCs). Extracellular adenosine triphosphate (eATP) plays the role in both inflammation and osteogenic differentiation. eATP involves in immunosuppressive action by increasing immunosuppressive molecules IDO and IFNγ expression on immune cells. However, the role of eATP on the immunomodulation of hPDLCs remains unclear. This study aimed to examine the effects of eATP on the IDO and IFNγ expression of hPDLCs and the participation of purinergic P2 receptors in this phenomenon. METHODS hPDLCs were treated with eATP. The mRNA and protein expression of indoleamine-pyrrole 2,3-dioxygenase (IDO) and interferon-gamma (IFNγ) were determined. The role of the purinergic P2 receptor was determined using calcium chelator (EGTA) and PKC inhibitor (PKCi). Chemical inhibitors (KN62 and BBG), small interfering RNA (siRNA), and P2 X7 receptor agonist (BzATP) were used to confirm the involvement of P2 X7 receptors on IDO and IFNγ induction by hPDLCs. RESULTS eATP significantly enhanced mRNA expression of IDO and IFNγ. Moreover, eATP increased kynurenine which is the active metabolite of tryptophan breakdown catalyzed by the IDO enzyme and significantly induced IFNγ protein expression. EGTA and PKCi reduced eATP-induced IDO and IFNγ expressions by hPDLCs, confirming the role of calcium signaling. Chemical P2 X7 inhibitors (KN62 and BBG) and siRNA targeting the P2 X7 receptor significantly inhibited the eATP-induced IDO and IFNγ production. Correspondingly, BzATP markedly increased IDO and IFNγ expression. CONCLUSION eATP induced immunosuppressive function of hPDLCs by promoting IDO and IFNγ production via P2 X7 receptor signaling. eATP may become a promising target for periodontal regeneration by modulating immune response and further triggering tissue healing.
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Affiliation(s)
- Maythwe Kyawsoewin
- Center of Excellence for Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand.,Department of Oral Biological Science, University of Dental Medicine, Yangon, Myanmar
| | - Phoonsuk Limraksasin
- Center of Excellence for Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand.,Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Utapin Ngaokrajang
- Center of Excellence for Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Prasit Pavasant
- Center of Excellence for Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand.,Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Thanaphum Osathanon
- Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Dental Stem Cell Biology Research Unit, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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McDew-White M, Lee E, Alvarez X, Sestak K, Ling BJ, Byrareddy SN, Okeoma CM, Mohan M. Cannabinoid control of gingival immune activation in chronically SIV-infected rhesus macaques involves modulation of the indoleamine-2,3-dioxygenase-1 pathway and salivary microbiome. EBioMedicine 2022; 75:103769. [PMID: 34954656 PMCID: PMC8715300 DOI: 10.1016/j.ebiom.2021.103769] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/28/2021] [Accepted: 12/07/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND HIV/SIV-associated periodontal disease (gingivitis/periodontitis) (PD) represents a major comorbidity affecting people living with HIV (PLWH) on combination anti-retroviral therapy (cART). PD is characterized by chronic inflammation and dysbiosis. Nevertheless, the molecular mechanisms and use of feasible therapeutic strategies to reduce/reverse inflammation and dysbiosis remain understudied and unaddressed. METHODS Employing a systems biology approach, we report molecular, metabolome and microbiome changes underlying PD and its modulation by phytocannabinoids [delta-9-tetrahydrocannabinol (Δ9-THC)] in uninfected and SIV-infected rhesus macaques (RMs) untreated (VEH-untreated/SIV) or treated with vehicle (VEH/SIV) or Δ9-THC (THC/SIV). FINDINGS VEH- untreated/SIV but not THC/SIV RMs showed significant enrichment of genes linked to anti-viral defense, interferon-β, NFκB, RIG-1, and JAK-STAT signaling. We focused on the anti-microbial DUOX1 and immune activation marker IDO1 that were reciprocally regulated in the gingiva of VEH-untreated/SIV RMs. Both proteins localized to the gingival epithelium and CD163+ macrophages, and showed differential expression in the gingiva of THC/SIV and VEH/SIV RMs. Additionally, inflammation-associated miR-21, miR-142-3p, miR-223, and miR-125a-5p showed significantly higher expression in the gingiva of VEH/SIV RMs. In human primary gingival epithelial cells, miR-125a-5p post-transcriptionally downregulated DUOX1 and THC inhibited IDO1 protein expression through a cannabinoid receptor-2 mediated mechanism. Interestingly, THC/SIV RMs showed relatively reduced plasma levels of kynurenine, kynurenate, and the neurotoxic quinolinate compared to VEH/SIV RMs at 5 months post SIV infection (MPI). Most importantly, THC blocked HIV/SIV-induced depletion of Firmicutes and Bacteroidetes, and reduced Gammaproteobacteria abundance in saliva. Reduced IDO1 protein expression was associated with significantly (p<0.05) higher abundance of Prevotella, Lactobacillus (L. salivarius, L. buchneri, L. fermentum, L. paracasei, L. rhamnosus, L. johnsonii) and Bifidobacteria and reduced abundance of the pathogenic Porphyromonas cangingivalis and Porphyromonas macacae at 5MPI. INTERPRETATION The data provides deeper insights into the molecular mechanisms underlying HIV/SIV-induced PD and more importantly, the anti-inflammatory and anti-dysbiotic properties of THC in the oral cavity. Overall, these translational findings suggest that phytocannabinoids may help reduce gingival/systemic inflammation, salivary dysbiosis and potentially metabolic disease/syndrome in PLWH on cART and those with no access to cART or do not suppress the virus under cART. FUNDING Research reported in this publication was supported by the National Institutes of Health Award Numbers R01DA052845 (MM and SNB), R01DA050169 (MM and CO), R01DA042524 and R56DE026930 (MM), and P51OD011104 and P51OD011133. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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Affiliation(s)
- Marina McDew-White
- Texas Biomedical Research Institute, Southwest National Primate Research Center, 8715 West Military Road, San Antonio, TX 78227, United States
| | - Eunhee Lee
- Texas Biomedical Research Institute, Southwest National Primate Research Center, 8715 West Military Road, San Antonio, TX 78227, United States
| | - Xavier Alvarez
- Texas Biomedical Research Institute, Southwest National Primate Research Center, 8715 West Military Road, San Antonio, TX 78227, United States
| | - Karol Sestak
- PreCliniTria, LLC., Mandeville, LA 70471, United States; Tulane National Primate Research Center, Covington LA 70433, United States
| | - Binhua J Ling
- Texas Biomedical Research Institute, Southwest National Primate Research Center, 8715 West Military Road, San Antonio, TX 78227, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Chioma M Okeoma
- Department of Pharmacology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794-8651, United States
| | - Mahesh Mohan
- Texas Biomedical Research Institute, Southwest National Primate Research Center, 8715 West Military Road, San Antonio, TX 78227, United States.
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Andrukhov O. Toll-Like Receptors and Dental Mesenchymal Stromal Cells. FRONTIERS IN ORAL HEALTH 2021; 2:648901. [PMID: 35048000 PMCID: PMC8757738 DOI: 10.3389/froh.2021.648901] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022] Open
Abstract
Dental mesenchymal stromal cells (MSCs) are a promising tool for clinical application in and beyond dentistry. These cells possess multilineage differentiation potential and immunomodulatory properties. Due to their localization in the oral cavity, these cells could sometimes be exposed to different bacteria and viruses. Dental MSCs express various Toll-like receptors (TLRs), and therefore, they can recognize different microorganisms. The engagement of TLRs in dental MSCs by various ligands might change their properties and function. The differentiation capacity of dental MSCs might be either inhibited or enhanced by TLRs ligands depending on their nature and concentrations. Activation of TLR signaling in dental MSCs induces the production of proinflammatory mediators. Additionally, TLR ligands alter the immunomodulatory ability of dental MSCs, but this aspect is still poorly explored. Understanding the role of TLR signaling in dental MSCs physiology is essential to assess their role in oral homeostasis, inflammatory diseases, and tissue regeneration.
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Affiliation(s)
- Oleh Andrukhov
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria
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10
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Wadhawan A, Reynolds MA, Makkar H, Scott AJ, Potocki E, Hoisington AJ, Brenner LA, Dagdag A, Lowry CA, Dwivedi Y, Postolache TT. Periodontal Pathogens and Neuropsychiatric Health. Curr Top Med Chem 2021; 20:1353-1397. [PMID: 31924157 DOI: 10.2174/1568026620666200110161105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 12/04/2019] [Accepted: 12/04/2019] [Indexed: 02/08/2023]
Abstract
Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.
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Affiliation(s)
- Abhishek Wadhawan
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States.,Department of Psychiatry, Saint Elizabeths Hospital, Washington, D.C. 20032, United States
| | - Mark A Reynolds
- Department of Advanced Oral Sciences & Therapeutics, University of Maryland School of Dentistry, Baltimore 21201, United States
| | - Hina Makkar
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States
| | - Alison J Scott
- Department of Microbial Pathogenesis, University of Maryland School of Dentistry, Baltimore, United States
| | - Eileen Potocki
- VA Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, United States
| | - Andrew J Hoisington
- Air Force Institute of Technology, Wright-Patterson Air Force Base, United States
| | - Lisa A Brenner
- Departments of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States
| | - Aline Dagdag
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States
| | - Christopher A Lowry
- Departments of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado Anschutz Medical Campus, Aurora, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States.,Department of Integrative Physiology, Center for Neuroscience and Center for Microbial Exploration, University of Colorado Boulder, Boulder, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, United States
| | - Yogesh Dwivedi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Alabama, United States
| | - Teodor T Postolache
- Mood and Anxiety Program, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, United States.,Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 19, Aurora, United States.,Military and Veteran Microbiome: Consortium for Research and Education (MVM-CoRE), Aurora, United States.,Mental Illness Research, Education and Clinical Center (MIRECC), Veterans Integrated Service Network (VISN) 5, VA Capitol Health Care Network, Baltimore, United States
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11
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Behm C, Blufstein A, Gahn J, Kubin B, Moritz A, Rausch-Fan X, Andrukhov O. Continuing Effect of Cytokines and Toll-Like Receptor Agonists on Indoleamine-2,3-Dioxygenase-1 in Human Periodontal Ligament Stem/Stromal Cells. Cells 2020; 9:2696. [PMID: 33339125 PMCID: PMC7765527 DOI: 10.3390/cells9122696] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/03/2020] [Accepted: 12/14/2020] [Indexed: 12/25/2022] Open
Abstract
Transplanted mesenchymal stem/stromal cells (MSCs) are a promising and innovative approach in regenerative medicine. Their regenerative potential is partly based upon their immunomodulatory activities. One of the most investigated immunomediators in MSCs, such as in periodontal ligament-derived MSCs (hPDLSCs), is indoleamine-2,3-dioxygenase-1 (IDO-1) which is upregulated by inflammatory stimuli, like cytokines. However, there are no data concerning continuing IDO-1 expression in hPDLSCs after the removal of inflammatory stimuli, such as cytokines and toll-like receptor (TLR) agonist-2 and TLR-3. Hence, primary hPDLSCs were stimulated with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, TLR-2 agonist Pam3CSK4 or TLR-3 agonist Poly I/C. IDO-1 gene and protein expression and its enzymatic activity were measured up to five days after removing any stimuli. IL-1β- and TNF-α-induced IDO-1 expression and enzymatic activity decreased in a time-dependent manner after cessation of stimulation. IFN-γ caused a long-lasting effect on IDO-1 up to five days after removing IFN-γ. Both, TLR-2 and TLR-3 agonists induced a significant increase in IDO-1 gene expression, but only TLR-3 agonist induced significantly higher IDO-1 protein expression and enzymatic activity in conditioned media (CM). IDO-1 activity of Poly I/C- and Pam3CSK4-treated hPDLSCs was higher at one day after removal of stimuli than immediately after stimulation and declined to basal levels after five days. Among all tested stimuli, only IFN-γ was able to induce long-lasting IDO-1 expression and activity in hPDLSCs. The high plasticity of IDO-1 expression and its enzymatic activity in hPDLSCs due to the variable cytokine and virulence factor milieu and the temporal-dependent responsiveness of hPDLSCs may cause a highly dynamic potential of hPDLSCs to modulate immune responses in periodontal tissues.
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Affiliation(s)
- Christian Behm
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
- Division of Orthodontics, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria
| | - Alice Blufstein
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria;
| | - Johannes Gahn
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
| | - Barbara Kubin
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
| | - Andreas Moritz
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria;
| | - Xiaohui Rausch-Fan
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria;
| | - Oleh Andrukhov
- Competence Center for Periodontal Research, University Clinic of Dentistry, Medical University of Vienna, Sensengasse 2a, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (X.R.-F.)
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12
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Behm C, Blufstein A, Gahn J, Nemec M, Moritz A, Rausch-Fan X, Andrukhov O. Cytokines Differently Define the Immunomodulation of Mesenchymal Stem Cells from the Periodontal Ligament. Cells 2020; 9:1222. [PMID: 32423044 PMCID: PMC7290931 DOI: 10.3390/cells9051222] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 05/05/2020] [Accepted: 05/11/2020] [Indexed: 12/11/2022] Open
Abstract
Human periodontal ligament stem cells (hPDLSCs) play an important role in periodontal tissue homeostasis and regeneration. The function of these cells in vivo depends largely on their immunomodulatory ability, which is reciprocally regulated by immune cells via cytokines, particularly interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-1β. Different cytokines activate distinct signaling pathways and might differently affect immunomodulatory activities of hPDLSCs. This study directly compared the effect of IFN-γ, TNF-α, or IL-1β treated primary hPDLSCs on allogenic CD4+ T lymphocyte proliferation and apoptosis in an indirect co-culture model. The effects of IFN-γ, TNF-α, and IL-1β on the expression of specific immunomodulatory factors such as intoleamine-2,3-dioxygenase-1 (IDO-1), prostaglandin E2 (PGE2), and programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2) in hPDLSCs were compared. The contribution of different immunomodulatory mediators to the immunomodulatory effects of hPDLSCs in the indirect co-culture experiments was assessed using specific inhibitors. Proliferation of CD4+ T lymphocytes was inhibited by hPDLSCs, and this effect was strongly enhanced by IFN-γ and IL-1β but not by TNF-α. Apoptosis of CD4+ T lymphocytes was decreased by hPDLSCs per se. This effect was counteracted by IFN-γ or IL-1β. Additionally, IFN-γ, TNF-α, and IL-1β differently regulated all investigated immunomediators in hPDLSCs. Pharmacological inhibition of immunomediators showed that their contribution in regulating CD4+ T lymphocytes depends on the cytokine milieu. Our data indicate that inflammatory cytokines activate specific immunomodulatory mechanisms in hPDLSCs and the expression of particular immunomodulatory factors, which underlies a complex reciprocal interaction between hPDLSCs and CD4+ T lymphocytes.
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Affiliation(s)
- Christian Behm
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
- Department of Orthodontics, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
| | - Alice Blufstein
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
| | - Johannes Gahn
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
| | - Michael Nemec
- Department of Orthodontics, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
| | - Andreas Moritz
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
| | - Xiaohui Rausch-Fan
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
| | - Oleh Andrukhov
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria; (C.B.); (A.B.); (J.G.); (A.M.); (X.R.-F.)
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13
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Chaikeawkaew D, Everts V, Pavasant P. TLR3 activation modulates immunomodulatory properties of human periodontal ligament cells. J Periodontol 2020; 91:1225-1236. [PMID: 31981371 DOI: 10.1002/jper.19-0551] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 12/23/2019] [Accepted: 12/23/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Toll-like receptors (TLR) are a group of receptors that play roles in the innate immune system. Human periodontal ligament cells (hPDL cells) express several TLRs, including TLR3, a nucleotide sensing receptor that recognizes double-stranded RNA from viral infection. However, its role in hPDL cells is unclear. The aim of this study was to investigate the responses of hPDL cells in terms of immunomodulation after TLR3 engagement. METHODS HPDL cells were treated with various doses of poly I:C, a TLR3 activator. The expression of interferon-gamma (IFNγ), indoleamine 2,3 dioxygenase (IDO), and human leukocyte antigen G (HLA-G) was determined. Chemical inhibitors and small interfering RNA (siRNA) were used to confirm the role of TLR3. Coculture with human peripheral blood mononuclear cells (PBMCs) with poly I:C-activated hPDL cells was performed. RESULTS Endosomal TLR3 in hPDL cells was observed by immunocytochemistry. Addition of poly I:C significantly enhanced the expression and secretion of IFNγ, IDO, and HLA-G. Knockdown of TLR3 using siRNA decreased the poly I:C-induced expression of these three molecules. Bafilomycin-A, an inhibitor of auto-phagosome and lysosome fusion, inhibited poly I:C-induced IDO and HLA-G expression, whereas cycloheximide and a TLR3-neutralizing antibody had no effect. In co-culture experiments, poly I:C-activated hPDL cells inhibited PBMCs proliferation and increased mRNA expression of forkhead box P3 (FOXP3), a transcription factor which is a marker of regulatory T cells. CONCLUSION Our findings indicated that TLR3 engagement of hPDL cells induced immunosuppressive properties of these cells. Because immunosuppressive properties play an important role in tissue healing and regeneration, activation of TLR3 may help to attenuate tissue destruction by limiting the inflammatory process and perhaps initiate the healing and regeneration process of the periodontium.
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Affiliation(s)
- Daneeya Chaikeawkaew
- Center of Excellence in Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Oral Biology Graduate Program, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Vincent Everts
- Department of Oral Cell Biology, Academic Center of Dentistry Amsterdam, University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands
| | - Prasit Pavasant
- Center of Excellence in Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand.,Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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14
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Behm C, Blufstein A, Gahn J, Kubin B, Nemec M, Moritz A, Rausch-Fan X, Andrukhov O. 1,25(OH) 2D 3 Differently Affects Immunomodulatory Activities of Mesenchymal Stem Cells Depending on the Presence of TNF-α, IL-1β and IFN-γ. J Clin Med 2019; 8:2211. [PMID: 31847340 PMCID: PMC6947512 DOI: 10.3390/jcm8122211] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/10/2019] [Accepted: 12/12/2019] [Indexed: 12/15/2022] Open
Abstract
Periodontal ligament-derived mesenchymal stem cells (hPDLSCs) possess immunomodulatory abilities which are strongly enhanced by various inflammatory cytokines. Vitamin D3 has anti-inflammatory effects on hPDLSCs and immune cells. However, no study to date has directly compared the influence of 1,25(OH)2D3 on the immunomodulatory activities of hPDLSCs in the presence of different cytokines. In the present study, the effects of hPDLSCs treated with tumor necrosis factor (TNF)-α, interleukin (IL)-1β, or interferon (IFN)-γ in the presence of 1,25(OH)2D3 on the proliferation of allogenic CD4+ T lymphocyte or on the functional status of primary CD68+ macrophages were analyzed in coculture models. Additionally, the effects of 1,25(OH)2D3 on TNF-α-, IL-1β-, and IFN-γ-induced gene expression of some immunomodulatory factors in hPDLSCs were compared. Under coculture conditions, 1,25(OH)2D3 increased or decreased CD4+ T lymphocyte proliferation via hPDLSCs, depending on the cytokine. hPDLSCs primed with 1,25(OH)2D3 and different cytokines affected pro- and anti-inflammatory cytokine expression in macrophages variably, depending on the priming cytokine. With one exception, 1,25(OH)2D3 significantly reduced TNF-α-, IL-1β-, and IFN-γ-induced expression of all the investigated immunomediators in hPDLSCs, albeit to different extents. These results suggest that 1,25(OH)2D3 influences the immunomodulatory activities of hPDLSCs depending qualitatively and quantitatively on the presence of certain inflammatory cytokines.
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Affiliation(s)
- Christian Behm
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Alice Blufstein
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Johannes Gahn
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Barbara Kubin
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Michael Nemec
- Clinical Division of Orthodontics, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria;
| | - Andreas Moritz
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Xiaohui Rausch-Fan
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
| | - Oleh Andrukhov
- Department of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, 1090 Wien, Austria; (C.B.); (A.B.); (J.G.); (B.K.); (A.M.); (X.R.-F.)
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15
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Andrukhov O, Behm C, Blufstein A, Rausch-Fan X. Immunomodulatory properties of dental tissue-derived mesenchymal stem cells: Implication in disease and tissue regeneration. World J Stem Cells 2019; 11:604-617. [PMID: 31616538 PMCID: PMC6789188 DOI: 10.4252/wjsc.v11.i9.604] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 04/24/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are considered as an attractive tool for tissue regeneration and possess a strong immunomodulatory ability. Dental tissue-derived MSCs can be isolated from different sources, such as the dental pulp, periodontal ligament, deciduous teeth, apical papilla, dental follicles and gingiva. According to numerous in vitro studies, the effect of dental MSCs on immune cells might depend on several factors, such as the experimental setting, MSC tissue source and type of immune cell preparation. Most studies have shown that the immunomodulatory activity of dental MSCs is strongly upregulated by activated immune cells. MSCs exert mostly immunosuppressive effects, leading to the dampening of immune cell activation. Thus, the reciprocal interaction between dental MSCs and immune cells represents an elegant mechanism that potentially contributes to tissue homeostasis and inflammatory disease progression. Although the immunomodulatory potential of dental MSCs has been extensively investigated in vitro, its role in vivo remains obscure. A few studies have reported that the MSCs isolated from inflamed dental tissues have a compromised immunomodulatory ability. Moreover, the expression of some immunomodulatory proteins is enhanced in periodontal disease and even shows some correlation with disease severity. MSC-based immunomodulation may play an essential role in the regeneration of different dental tissues. Therefore, immunomodulation-based strategies may be a very promising tool in regenerative dentistry.
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Affiliation(s)
- Oleh Andrukhov
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria.
| | - Christian Behm
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
| | - Alice Blufstein
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
| | - Xiaohui Rausch-Fan
- Division of Conservative Dentistry and Periodontology, University Clinic of Dentistry, Medical University of Vienna, Vienna 1090, Austria
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16
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Acovic A, Gazdic M, Jovicic N, Harrell CR, Fellabaum C, Arsenijevic N, Volarevic V. Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract. Therap Adv Gastroenterol 2018; 11:1756284818815334. [PMID: 30574192 PMCID: PMC6295700 DOI: 10.1177/1756284818815334] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 10/31/2018] [Indexed: 02/04/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO) has the most important role in modulation of tryptophan-dependent effects in the gastrointestinal tract, including modulation of intestinal immune response. An increased IDO activity maintains immune tolerance and attenuates ongoing inflammation but allows immune escape and uncontrolled growth of gastrointestinal tumors. Accordingly, IDO represents a novel therapeutic target for the treatment of inflammatory and malignant diseases of the gastrointestinal tract. In this review article, we summarize current knowledge about molecular and cellular mechanisms that are involved in IDO-dependent effects. We provide a brief outline of experimental and clinical studies that increased our understanding of how enhanced IDO activity: controls host-microbiota interactions in the gut; regulates detrimental immune response in inflammatory disorders of the gastrointestinal system; and allows immune escape and uncontrolled growth of gastrointestinal tumors. Additionally, we present future perspectives regarding modulation of IDO activity in the gut as possible new therapeutic approaches for the treatment of inflammatory and malignant diseases of the gastrointestinal system.
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Affiliation(s)
- Aleksandar Acovic
- Center for Molecular Medicine and Stem Cell Research, Department of Microbiology and Immunology, Faculty of Medical Sciences University of Kragujevac, Kragujevac, Serbia
| | - Marina Gazdic
- Center for Molecular Medicine and Stem Cell Research, Department of Microbiology and Immunology, Faculty of Medical Sciences University of Kragujevac, Kragujevac, Serbia
| | - Nemanja Jovicic
- Center for Molecular Medicine and Stem Cell Research, Department of Microbiology and Immunology, Faculty of Medical Sciences University of Kragujevac, Kragujevac, Serbia
| | | | - Crissy Fellabaum
- Regenerative Processing Plant-RPP, LLC, Palm Harbor, Florida, USA
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Department of Microbiology and Immunology, Faculty of Medical Sciences University of Kragujevac, Kragujevac, Serbia
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17
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Arjunan P, Meghil MM, Pi W, Xu J, Lang L, El-Awady A, Sullivan W, Rajendran M, Rabelo MS, Wang T, Tawfik OK, Kunde-Ramamoorthy G, Singh N, Muthusamy T, Susin C, Teng Y, Arce RM, Cutler CW. Oral Pathobiont Activates Anti-Apoptotic Pathway, Promoting both Immune Suppression and Oncogenic Cell Proliferation. Sci Rep 2018; 8:16607. [PMID: 30413788 PMCID: PMC6226501 DOI: 10.1038/s41598-018-35126-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/30/2018] [Indexed: 12/25/2022] Open
Abstract
Chronic periodontitis (CP) is a microbial dysbiotic disease linked to increased risk of oral squamous cell carcinomas (OSCCs). To address the underlying mechanisms, mouse and human cell infection models and human biopsy samples were employed. We show that the ‘keystone’ pathogen Porphyromonas gingivalis, disrupts immune surveillance by generating myeloid-derived dendritic suppressor cells (MDDSCs) from monocytes. MDDSCs inhibit CTLs and induce FOXP3 + Tregs through an anti-apoptotic pathway. This pathway, involving pAKT1, pFOXO1, FOXP3, IDO1 and BIM, is activated in humans with CP and in mice orally infected with Mfa1 expressing P. gingivalis strains. Mechanistically, activation of this pathway, demonstrating FOXP3 as a direct FOXO1-target gene, was demonstrated by ChIP-assay in human CP gingiva. Expression of oncogenic but not tumor suppressor markers is consistent with tumor cell proliferation demonstrated in OSCC-P. gingivalis cocultures. Importantly, FimA + P. gingivalis strain MFI invades OSCCs, inducing inflammatory/angiogenic/oncogenic proteins stimulating OSCCs proliferation through CXCR4. Inhibition of CXCR4 abolished Pg-MFI-induced OSCCs proliferation and reduced expression of oncogenic proteins SDF-1/CXCR4, plus pAKT1-pFOXO1. Conclusively, P. gingivalis, through Mfa1 and FimA fimbriae, promotes immunosuppression and oncogenic cell proliferation, respectively, through a two-hit receptor-ligand process involving DC-SIGN+hi/CXCR4+hi, activating a pAKT+hipFOXO1+hiBIM−lowFOXP3+hi and IDO+hi- driven pathway, likely to impact the prognosis of oral cancers in patients with periodontitis.
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Affiliation(s)
- Pachiappan Arjunan
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America.
| | - Mohamed M Meghil
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America.,Department of Oral Biology, Augusta University, Augusta, Georgia, United States of America
| | - Wenhu Pi
- Department of Radiation Oncology, Indiana University, Indianapolis, Indiana, United States of America
| | - Jinxian Xu
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - Liwei Lang
- Department of Oral Biology, Augusta University, Augusta, Georgia, United States of America
| | - Ahmed El-Awady
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - William Sullivan
- Department of Energy, Joint Genome Institute, California, United States of America
| | - Mythilypriya Rajendran
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - Mariana Sousa Rabelo
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America.,Department of Periodontics, University of São Paulo, Sao Paulo, Brazil
| | - Tong Wang
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - Omnia K Tawfik
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | | | - Nagendra Singh
- Department of Biochemistry & Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Thangaraju Muthusamy
- Department of Biochemistry & Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Cristiano Susin
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - Yong Teng
- Department of Oral Biology, Augusta University, Augusta, Georgia, United States of America
| | - Roger M Arce
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America
| | - Christopher W Cutler
- Department of Periodontics, Dental College of Georgia, Augusta University, Augusta, Georgia, United States of America.
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Allison DJ, Josse AR, Gabriel DA, Klentrou P, Ditor DS. Targeting inflammation to influence cognitive function following spinal cord injury: a randomized clinical trial. Spinal Cord 2016; 55:26-32. [PMID: 27324320 DOI: 10.1038/sc.2016.96] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 04/29/2016] [Accepted: 05/17/2016] [Indexed: 11/09/2022]
Abstract
STUDY DESIGN This study was a randomized, parallel-group, controlled clinical trial. OBJECTIVES The purpose of this study was to examine the efficacy of targeting inflammation as a means of improving cognitive function in individuals with spinal cord injury. SETTING Participants were recruited from the Niagara region of Ontario Canada and all testing occurred on-site at Brock University. METHODS Indices of memory and verbal learning were assessed by means of the California Verbal Learning Test (CVLT). Inflammation and concentrations of neuroactive compounds related to the kynurenine pathway were assessed via a number of pro- and anti-inflammatory cytokines, as well as tryptophan, kynurenine and several large neutral amino acids. All assessments were performed at baseline as well as at 1 month and 3 months during a 3-month intervention by means of an anti-inflammatory diet. RESULTS Despite a reduction in inflammation, all measures of the CVLT, including list A, trial 1 (P=0.48), learning slope (P=0.46), long delay free recall (P=0.83), intrusions (P=0.61) and repetitions (P=0.07), showed no significant group × time interaction. CONCLUSION It may be possible that the reduction in inflammation achieved in the current study was insufficient to induce substantial changes in indices of verbal learning and memory. Alternatively, as these participants likely underwent years of previous chronic inflammation, the underlying hippocampal damage may have negated potential improvements induced by acute reductions in inflammation.
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Affiliation(s)
- D J Allison
- Department of Kinesiology, Brock University, St Catharines, Ontario, Canada.,Brock-Niagara Centre for Health and Well-Being, St Catharines, Ontario, Canada
| | - A R Josse
- Department of Kinesiology, Brock University, St Catharines, Ontario, Canada
| | - D A Gabriel
- Department of Kinesiology, Brock University, St Catharines, Ontario, Canada
| | - P Klentrou
- Department of Kinesiology, Brock University, St Catharines, Ontario, Canada
| | - D S Ditor
- Department of Kinesiology, Brock University, St Catharines, Ontario, Canada.,Brock-Niagara Centre for Health and Well-Being, St Catharines, Ontario, Canada
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19
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Qin X, Liu JY, Wang T, Pashley DH, Al-Hashim AH, Abdelsayed R, C Yu J, Mozaffari MS, Baban B. Role of indoleamine 2,3-dioxygenase in an inflammatory model of murine gingiva. J Periodontal Res 2016; 52:107-113. [PMID: 27005943 DOI: 10.1111/jre.12374] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND OBJECTIVE Indoleamine 2,3-dioxygenase (IDO) is one of the major pathways for metabolism of tryptophan in a variety of cells, including immune cells. Increasing evidence indicates that IDO is a critical player in establishing the balance between immunity and tolerance and ultimately in the maintenance of homeostasis. By inducing inflammation in gingival tissue, we tested the hypothesis that IDO is a pivotal player in regulating the immune and inflammatory responses of gingiva. MATERIAL AND METHODS We utilized the IDO knockout mouse model in conjunction with lipopolysaccharide (LPS)-induced inflammation. Accordingly, wild-type and IDO knockout mice were injected with LPS or vehicle in the anterior mandibular gingiva, twice over a 2-wk period, which was followed by procurement of gingival tissue for histopathology and preparation of tissue for flow cytometry-based studies. RESULTS Clinical and histological examinations revealed a marked adverse impact of IDO deficiency on gingival inflammation. These observations were consistent with a more marked increase in the number of cells positive for the proinflammatory cytokine interleukin (IL)-17, but no significant change in the number of cells positive for the anti-inflammatory cytokine IL-10, in LPS-treated IDO knockout mice. Consistent with the more marked proinflammatory impact of IDO deficiency, the percentage of regulatory T cells was much reduced in gingival tissue of LPS-treated IDO knockout mice than in gingival tissue of wild-type mice. These proinflammatory changes were accompanied with a prominent increase in apoptotic and necrotic cell death in gingival tissue of IDO knockout mice compared with wild-type mice. CONCLUSION Collectively, our findings support a major role for IDO in the development of gingival inflammation, as an example of an inflammatory condition, and lay the foundation for subsequent studies to explore it as a novel immunotherapy target.
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Affiliation(s)
- X Qin
- Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - J Y Liu
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - T Wang
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.,The 3rd Department, Plastic Surgery Hospital (Institute), CAMS&PUMC, Beijing, China
| | - D H Pashley
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - A H Al-Hashim
- Department of Oral Rehabilitation, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - R Abdelsayed
- Department of Oral Health and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - J C Yu
- Department of Surgery, Section of Plastic Surgery, School of Medicine, Augusta University, Augusta, GA, USA
| | - M S Mozaffari
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - B Baban
- Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, USA.,Department of Surgery, Section of Plastic Surgery, School of Medicine, Augusta University, Augusta, GA, USA
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20
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Moretti S, Bartolommei L, Galosi C, Renga G, Oikonomou V, Zamparini F, Ricci G, Borghi M, Puccetti M, Piobbico D, Eramo S, Conti C, Lomurno G, Bartoli A, Napolioni V, Romani L. Fine-tuning of Th17 Cytokines in Periodontal Disease by IL-10. J Dent Res 2015; 94:1267-75. [PMID: 26092379 DOI: 10.1177/0022034515591790] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Periodontitis (PD) is a chronic disease caused by the host inflammatory response to bacteria colonizing the oral cavity. In addition to tolerance to oral microbiome, a fine-tuned balance of IL-10 levels is critical to efficiently mount antimicrobial resistance without causing immunopathology. Clinical and animal studies support that adaptive T-helper (Th) cytokines are involved in the pathogenesis of alveolar bone destruction in PD. However, it remains unclear what type of Th response is related to human PD progression and what role IL-10 has on this process. We addressed the contribution of IL-10 in limiting Th1 and Th17 inflammatory response in murine and human PD. Through a combination of basic and translational approaches involving selected cytokine-deficient mice as well as human genetic epidemiology, our results demonstrate the requirement for IL-10 in fine-tuning the levels of Th17 (IL-17A and IL-17F) cytokines in experimental and human PD. Of novelty, we found that IL-17F correlated with protection in murine and human PD and was positively regulated by IL-10. To our knowledge, this is the first demonstration of the protective role for IL-17F in PD, its positive regulation by IL-10, and the potential differential role for IL-17A and IL-17F in periodontal disease.
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Affiliation(s)
- S Moretti
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - L Bartolommei
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - C Galosi
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - G Renga
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - V Oikonomou
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - F Zamparini
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - G Ricci
- Department of Veterinary Pathology, University of Perugia, Perugia, Italy
| | - M Borghi
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - M Puccetti
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - D Piobbico
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - S Eramo
- Department of Surgical and Biochemical Sciences, University of Perugia, Perugia, Italy
| | - C Conti
- Dental Clinic, Ospedale Santa Maria della Misericordia, Perugia, Italy
| | - G Lomurno
- Dental Clinic, Ospedale Santa Maria della Misericordia, Perugia, Italy
| | - A Bartoli
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - V Napolioni
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - L Romani
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
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21
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Takegawa D, Nakanishi T, Hirao K, Yumoto H, Takahashi K, Matsuo T. Modulatory roles of interferon-γ through indoleamine 2, 3-dioxygenase induction in innate immune response of dental pulp cells. J Endod 2014; 40:1382-7. [PMID: 25146019 DOI: 10.1016/j.joen.2014.03.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/31/2014] [Accepted: 03/21/2014] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Marked infiltration of inflammatory cells such as activated T cells producing interferon-γ (IFN-γ) is observed in severe pulpitis. However, the roles of IFN-γ in the innate immune response of dental pulp have not been reported. Indoleamine 2, 3-dioxygenase (IDO) is a regulator of immune responses, and the IDO expression is induced by IFN-γ in many cells whose expression in dental pulp is unknown. The purpose of this study was to determine the role of IFN-γ in the immune response through microbial pattern recognition receptors (PRRs) such as Toll-like receptors or nucleotide-binding oligomerization domain-like receptors on the production of proinflammatory cytokines such as CXCL10 and interleukin (IL)-6 and the expression of IDO in cultured human dental pulp cells (HDPCs). METHODS HDPCs were established from explant cultures of healthy pulp tissues. CXCL10 and IL-6 production was determined using enzyme-linked immunosorbent assay. Confirmation of IDO localization in dental pulp tissues was examined using immunohistochemistry. IDO expression in HDPCs was analyzed by immunoblot. RESULTS IFN-γ significantly up-regulated CXCL10 and IL-6 production in the HDPCs stimulated with ligands for PRRs in a concentration-dependent manner. The expression of IDO was detected in inflamed pulp tissue. In addition, IFN-γ in combination with the PRR ligands enhanced IDO expression in HDPCs compared with IFN-γ alone. Moreover, CXCL10 production in IFN-γ-stimulated HDPCs was inhibited by an IDO inhibitor. CONCLUSIONS This study showed the synergistic effects by IFN-γ on cytokine production and IDO expression in HDPCs, suggesting that IFN-γ may modulate the innate immune response of dental pulp.
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Affiliation(s)
- Daisuke Takegawa
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Tadashi Nakanishi
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
| | - Kouji Hirao
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Hiromichi Yumoto
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Kanako Takahashi
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Takashi Matsuo
- Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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22
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Fournier BPJ, Larjava H, Häkkinen L. Gingiva as a source of stem cells with therapeutic potential. Stem Cells Dev 2013; 22:3157-77. [PMID: 23944935 DOI: 10.1089/scd.2013.0015] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Postnatal connective tissues contain phenotypically heterogeneous cells populations that include distinct fibroblast subpopulations, pericytes, myofibroblasts, fibrocytes, and tissue-specific mesenchymal stem cells (MSCs). These cells play key roles in tissue development, maintenance, and repair and contribute to various pathologies. Depending on the origin of tissue, connective tissue cells, including MSCs, have different phenotypes. Understanding the identity and specific functions of these distinct tissue-specific cell populations may allow researchers to develop better treatment modalities for tissue regeneration and find novel approaches to prevent pathological conditions. Interestingly, MSCs from adult oral mucosal gingiva possess distinct characteristics, including neural crest origin, multipotent differentiation capacity, fetal-like phenotype, and potent immunomodulatory properties. These characteristics and an easy, relatively noninvasive access to gingival tissue, and fast tissue regeneration after tissue biopsy make gingiva an attractive target for cell isolation for therapeutic purposes aiming to promote tissue regeneration and fast, scar-free wound healing. The purpose of this review is to discuss the identity, phenotypical heterogeneity, and function of gingival MSCs and summarize what is currently known about their properties, role in scar-free healing, and their future therapeutic potential.
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Affiliation(s)
- Benjamin P J Fournier
- 1 Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia , Vancouver, Canada
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23
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Moon JS, Cheong NR, Yang SY, Kim IS, Chung HJ, Jeong YW, Park JC, Kim MS, Kim SH, Ko HM. Lipopolysaccharide-induced indoleamine 2,3-dioxygenase expression in the periodontal ligament. J Periodontal Res 2013; 48:733-9. [PMID: 23488665 DOI: 10.1111/jre.12063] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVE Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-oxidizing enzyme with immune-inhibitory effects. The aim of this study was to investigate the expression of IDO by lipopolysaccharide (LPS), a component of gram-negative bacteria, in human periodontal ligament (PDL) cells. MATERIAL AND METHODS Human PDL cells and gingival fibroblasts (GFs) were prepared from explants of human PDLs and from gingival tissues of clinically healthy donors, respectively. Real-time RT-PCR, western blotting and the IDO enzyme assay were performed to determine the expression of IDO following LPS treatment of cells. LPS was injected into mice tail veins to evaluate the effects of LPS in vivo in the maxillary first molar. Immunofluorescence staining and histological analysis were followed to localize IDO in mouse PDL. RESULTS The level of expression of IDO mRNA in primary human PDL cells after LPS treatment was increased in a dose-dependent manner, reaching a peak 8 h after LPS treatment. The expression and activities of IDO protein were significantly increased in comparison with those of the control. In addition, the increased production of kynurenine in culture medium was observed 72 h after LPS treatment. In the immunofluorescence findings, stronger immunoreactivities were shown in PDL than in gingival tissues in the maxillae. In accordance with the immunofluorescence findings, LPS treatment induced a strong up-regulation of IDO mRNA in human PDL cells, whereas human GFs showed only a weak response to LPS. CONCLUSION These results clearly show that IDO was induced by LPS in primary human PDL cells, suggesting that PDL might be involved in the regulation of oral inflammatory disease.
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Affiliation(s)
- J S Moon
- Department of Oral Anatomy, Dental Science Research Institute, School of Dentistry, 2nd stage Brain Korea, Medical Research Center for Biomineralization Disorders, Chonnam National University, Gwangju, South Korea
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24
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Cutrim ES, Peruzzo DC, Benatti B. Evaluation of Soft Tissues Around Single Tooth Implants in the Anterior Maxilla Restored With Cemented and Screw-Retained Crowns. J ORAL IMPLANTOL 2012; 38:700-5. [DOI: 10.1563/aaid-joi-d-11-00125] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Implant-supported restorations can be attached as screw-retained or cemented prostheses. In both situations, the characteristics of the soft tissues around the implants are crucial for oral rehabilitation and patient satisfaction. Therefore, this study uses the Pink Esthetic Score (PES), which allows evaluation of gingival esthetics around implants, to evaluate the soft tissues around implants in the anterior maxilla rehabilitated with cemented prostheses (CP) and screw-retained prostheses (SP). Forty implants placed in the anterior maxilla were evaluated, and these had been rehabilitated with prosthetic crowns for a minimum of 1 year. Periodontal examination was performed to evaluate probing depth (PD) and bleeding on probing (BOP) of the implant and the corresponding natural tooth. The total mean (±SD) PES for SP was 10.73 (±1.98) and 10.41 (±2.67) for CP, which was not statistically significant (P ≥ .05). Periodontal examination revealed that CP and SP showed no difference for BOP (P ≥ .05). Differences were only detected in PD when comparing the reference teeth of both groups to CP and SP (P ≤ .05). The present study demonstrates that the PES proved to be an efficient index to assess peri-implant tissues, and that the type of crown retention does not influence the health and quality of the soft tissues around implants.
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Affiliation(s)
| | - Daiane Cristina Peruzzo
- Department of Periodontics, Faculty of Dentistry and Dental Research Center, São Leopoldo Mandic, São Paulo, Brazil
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25
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Konermann A, Beyer M, Deschner J, Allam JP, Novak N, Winter J, Jepsen S, Jäger A. Human periodontal ligament cells facilitate leukocyte recruitment and are influenced in their immunomodulatory function by Th17 cytokine release. Cell Immunol 2012; 272:137-43. [PMID: 22119482 DOI: 10.1016/j.cellimm.2011.10.020] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 08/18/2011] [Accepted: 10/24/2011] [Indexed: 12/12/2022]
Abstract
The objective of this in vitro study was to examine the immunomodulatory impact of human periodontal ligament (PDL) cells on the nature and magnitude of the leukocyte infiltrate in periodontal inflammation, particularly with regard to Th17 cells. PDL cells were challenged with pro-inflammatory cytokines (IL-1ß, IL-17A, and IFN-γ) and analyzed for the expression of cytokines involved in periodontal immunoinflammatory processes (IL-6, MIP-3 alpha, IL-23A, TGFß1, IDO, and CD274). In order to further investigate a direct involvement of PDL cells in leukocyte function, co-culture experiments were conducted. The expression of the immunomodulatory cytokines studied was significantly increased under pro-inflammatory conditions in PDL cells. Although PDL cells did not stimulate leukocyte proliferation or Th17 differentiation, these cells induced the recruitment of leukocytes. The results of our study suggest that PDL cells might be involved in chronic inflammatory mechanisms in periodontal tissues and thus in the transition to an adaptive immune response in periodontitis.
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Affiliation(s)
- A Konermann
- Department of Orthodontics, University of Bonn, Welschnonnenstr. 17, D-53111 Bonn, Germany
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26
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de Souza FRS, Fontes FL, da Silva TA, Coutinho LG, Leib SL, Agnez-Lima LF. Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis. BMC MEDICAL GENETICS 2011; 12:51. [PMID: 21473761 PMCID: PMC3084162 DOI: 10.1186/1471-2350-12-51] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 04/07/2011] [Indexed: 12/16/2022]
Abstract
Background The kynurenine (KYN) pathway has been shown to be altered in several diseases which compromise the central nervous system (CNS) including infectious diseases such as bacterial meningitis (BM). The aim of this study was to assess single nucleotide polymorphisms (SNPs) in four genes of KYN pathway in patients with meningitis and their correlation with markers of immune response in BM. Methods One hundred and one individuals were enrolled in this study to investigate SNPs in the following genes: indoleamine-2,3-dioxygenase (IDO1 gene), kynureninase (KYNU gene), kynurenine aminotransferase I (CCBL1 gene), and kynurenine aminotransferase II (AADAT gene). SNP analyses were performed by primer-introduced restriction analysis-PCR (PIRA-PCR) followed by RFLP. Cytokines were measured using multiplex bead assay while immunoglobulins (IG) by immunodiffusion plates and NF-kappaB and c-Jun by dot blot assay. Results The variant allele of SNP AADAT+401C/T showed prevalent frequency in patients with BM. A significant decrease (p < 0.05) in TNF-α, IL-1β, IL-6, MIP-1αCCL3 and MIP-1β/CCL4 levels was observed in BM patients homozygous (TT) to the SNP AADAT+401C/T. Furthermore, a significant (p < 0.05) decrease in cell count was observed in cerebrospinal fluid (CSF) from patients with TT genotype. In addition, an increase in the IgG level in adults (p < 0.05) was observed. The variant allele for KYNU+715G/A was found with low frequency in the groups, and the SNPs in IDO1+434T/G, KYNU+693G/A, CCBL1+164T/C, and AADAT+650C/T had no frequency in this population. Conclusions This study is the first report of an association of SNP AADAT+401C/T with the host immune response to BM, suggesting that this SNP may affect the host ability in recruitment of leukocytes to the infection site. This finding may contribute to identifying potential targets for pharmacological intervention as adjuvant therapy for BM.
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27
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Wang Y, Lawson MA, Dantzer R, Kelley KW. LPS-induced indoleamine 2,3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia. Brain Behav Immun 2010; 24:201-9. [PMID: 19577630 PMCID: PMC2818058 DOI: 10.1016/j.bbi.2009.06.152] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 06/25/2009] [Accepted: 06/29/2009] [Indexed: 01/03/2023] Open
Abstract
Inflammation-induced activation of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) causes depressive-like behavior in mice following acute activation of the innate immune system by lipopolysaccharide (LPS). Here we investigated the mechanism of IDO expression induced by LPS in primary cultures of microglia derived from neonatal C57BL/6J mice. LPS (10 ng/ml) induced IDO transcripts that peaked at 8h and enzymatic activity at 24h, resulting in an increase in extracellular kynurenine, the catabolic product of IDO-induced tryptophan catabolism. This IDO induction by LPS was accompanied by synthesis and secretion of the proinflammatory cytokines TNFalpha and IL-6, but without detectable IFNgamma expression. To explore the mechanism of LPS-induced IDO expression, microglia were pretreated with the c-Jun-N-terminal kinase (JNK) inhibitor SP600125 for 30 min before LPS treatment. We found that SP600125 blocked JNK phosphorylation and significantly decreased IDO expression induced by LPS, which was accompanied by a reduction of LPS-induced expression of TNFalpha and IL-6. Collectively, these data extend to microglia the property that LPS induces IDO expression via an IFNgamma-independent mechanism that depends upon activation of JNK. Inhibition of the JNK pathway may provide a new therapy for inflammatory depression.
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Affiliation(s)
- Yunxia Wang
- Department of Animal Sciences, Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 W. Gregory Drive, Urbana, IL 61801-3873, USA.
| | - Marcus A. Lawson
- Department of Animal Sciences, Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 W. Gregory Drive, Urbana, IL 61801-3873, USA
| | - Robert Dantzer
- Department of Animal Sciences, Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 W. Gregory Drive, Urbana, IL 61801-3873, USA,Department of Pathology, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Keith W. Kelley
- Department of Animal Sciences, Integrative Immunology and Behavior Program, University of Illinois at Urbana-Champaign, 227 Edward R. Madigan Laboratory, 1201 W. Gregory Drive, Urbana, IL 61801-3873, USA,Department of Pathology, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA,Corresponding authors: Keith W. Kelley, 227 Edward R. Madigan Laboratory, 1201 W. Gregory Dr., University of Illinois at Urbana-Champaign, Urbana, IL 61801-3873. Tel: (217) 333-5141, Fax: (217) 244-5617, or Yunxia Wang, 800 Xiangyin Road, Department of Nautical Medicine, Second Military Medical University, Shanghai, China 200433,
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