Exosomes derived from 3D-cultured MSCs improve therapeutic effects in periodontitis and experimental colitis and restore the Th17 cell/Treg balance in inflamed periodontium.
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ABSTRACT:
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8671433 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mesenchymal stem cells (MSCs) are multi-potent cells that are self-renewable and possess the potential to differentiate into multiple lineages. Several studies demonstrated that MSCs could regulate a Th17/Treg balance and could be a potential therapeutic target for Rheumatoid Arthritis (RA). A20 is highly expressed in many cell types after the stimulation of TNF-α, where it may inhibit pro-inflammatory cytokine secretion. However, the expression of A20 in BM-MSCs in RA is not fully understood. In our study, we found that A20 was decreased in RA patients' bone marrow MSCs (BM-MSCs), and with more IL-6 secretion, the balance of Th17/Treg was broken. In CIA mice, we found a moderate A20 decrease in mice MSCs as compared with those of control group in mRNA and protein levels. However, the IL-6 expression was increased. After umbilical cord MSCs treatment, A20 and IL-6 expressions were equal to the control group. Thus, our study indicates that loss of A20 in MSCs regulates the Th17/Treg balance in RA and the regulatory role of A20 in pro-inflammatory IL-6 production could be a potential target for the transfer of MSCs in RA adoptive therapy.
| S-EPMC5765124 | biostudies-literature
Project description:ObjectiveThis study investigated the peripheral Th17/Treg balance and its potential controlling factor indoleamine 2,3 dioxygenase (IDO) in patients with periodontitis and atherosclerosis (AS), as well as its correlation with Porphyromonas gingivalis infection.MethodsIn this retrospective study, P. gingivalis-infected atherosclerotic patients (Pg-AS), atherosclerotic patients (AS), P. gingivalis-infected periodontitis patients (Pg), and healthy controls (HCs) were selected after clinical examination, subgingival plaque examination, and plasma anti-P. gingivalis antibody analysis. Treg and Th17 cell percentages, related transcription factors, and functional cytokines in peripheral blood were analysed. Plasma tryptophan (Trp) and kynurenine (Kyn) were measured to determine IDO activity.ResultsAtherosclerotic patients (Pg-AS and AS groups) had significantly lower IDO activity and higher Th17/Treg ratio than those in the Pg and HC groups. The Th17/Treg ratio was higher and IDO activity was lower in the Pg-AS group compared with the AS group. Transcription factors and cytokines exhibited the same trend as the Th17 and Treg cells. Additionally, IDO activity was negatively correlated with the plasma anti-P. gingivalis antibody titre and the Th17/Treg ratio in the atherosclerotic group.ConclusionsP. gingivalis may reduce IDO activity and further promote Th17/Treg imbalance to facilitate AS development. IDO may be a novel molecular marker to predict periodontitis-associated AS.
| S-EPMC8894972 | biostudies-literature
Project description:N-3 polyunsaturated fatty acids (PUFA) have anti-inflammatory effects and were considered useful for the treatment of rheumatoid arthritis (RA). Recently, several studies suggested that n-3 PUFAs attenuated arthritis in animal model and human, however the mechanism is still unclear. Interleukin 17 (IL-17) is a pro-inflammatory cytokine mainly produced by T helper 17 (Th17) cells which cause tissue inflammation and bone erosion leading to joint destruction. In contrast, regulatory T (Treg) cells down-regulate various immune responses by suppression of naïve T cells. The imbalance between Th17 cells and Tregs cell is important for the pathogenesis of RA. Here, we investigated whether n-3 PUFAs attenuate arthritis in collagen antibody-induced arthritis (CAIA) model. We used fat-1 transgenic mice expressing the Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase that converts n-6 to n-3 fatty acids, leading to abundant n-3 fatty acids without the need of a dietary n-3 supply. Clinical arthritis score was significantly attenuated in fat-1 mice compared to wild type (WT) mice on day 7 (1.6±1.8, p = 0.012) and day 9 (1.5±1.6, p = 0.003). Ankle thickness also decreased significantly in fat-1 mice compared to WT mice (1.82±0.11, p = 0.008). The pathologic finding showed that inflammatory cell infiltration and bone destruction were reduced in fat-1 mice compared to WT. The expression levels of IL-17 and related cytokines including IL-6 and IL-23 decreased in the spleen and ankle joint tissue of fat-1 mice compared to WT mice. Furthermore, Treg cells were expanded in the spleen of fat-1 mice and Treg cell differentiation was significantly higher in fat-1 mice than in wild type (p = 0.038). These data suggest that n-3 PUFAs could attenuate arthritis through increasing the expression of FoxP3 and the differentiation of Treg, while reducing IL-17 production. Therefore, dietary supplementation of n-3 PUFAs could have a therapeutic potential for the treatment of RA.
| S-EPMC5854360 | biostudies-literature
Project description:Object: The aims of the study were to explore the protective effects of S-propargyl-cysteine (SPRC) on periodontitis and to determine the underlying mechanisms. Methods: A rat periodontitis model was constructed by injecting LPS and SPRC (0, 25, and 50 mg/kg/d) was administered intraperitoneally. H2S and CSE level were detected. The alveolar bone level was evaluated by micro-CT, HE staining and methylene blue staining analysis. Inflammation-related factors, Treg and Th17 cells were detected by immunohistochemistry, RT-PCR, immunofluorescence, Western blot and flow cytometry. Phosphorylation levels of ERK1/2 and CREB were analysed. Results: The administration of SPRC significantly increased the expression of CSE in the gingival tissue and the concentration of endogenous H2S in the peripheral blood. Simultaneously, SPRC significantly inhibited the resorption of alveolar bone based on the H&E staining, micro-CT and methylene blue staining analysis. Compared with the periodontitis group, the levels of IL-17A, IL-10 were downregulated and IL-6,TGF-β1 were upregulated in the SPRC groups. In the SPRC group, the percentage of TH17 cells and the expression of ROR-γt were downregulated, while the percentage of Tregs and the expression of Foxp3 were upregulated accompanied with inhibition of phosphorylation ERK1/2 and CREB. Conclusion: SPRC can prevent the progression of periodontitis by regulating the Th17/Treg balance by inhibition of the ERK/CREB signalling pathway.
| S-EPMC8787365 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) and periodontitis are common and interrelated diseases, resulting in altered host response microbiota. The subgingival micro-organisms play a key role in periodontitis pathogenesis. To assess the shift of subgingival microbiome and metabolome in T2DM, we performed an analysis of the subgingival microbiome in patients with T2DM (n = 20) compared with non-diabetes (ND) subjects (n = 21). Furthermore, patients were subdivided into 10 T2DM with periodontitis (DP), 10 T2DM without periodontitis (DNP), 10 periodontitis (P), and 11 healthy control (H) groups. 16SrRNA gene sequencing combined with ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS) based metabolomics was performed in all participants. T lymphocyte immunity was analyzed by flow cytometry. Furthermore, the network relationship among subgingival micro-organisms, metabolites, blood glucose level, and T lymphocyte immunity were analyzed. The results showed that the difference of the subgingival microbiome from healthy to periodontitis status was less prominent in T2DM compared with ND, though the clinical signs of disease were similar. The bacteria Eubacterium nodatum group, Filifactor, Fretibacterium, Peptostreptococcus, and Desulfovibrio, amongst others, may be important in the pathopoiesia of periodontitis in the T2DM state. In addition, some dominant bacteria showed network relationships. The Treg/Th17 ratio was lower in the DP and DNP groups than in the P and H groups-though that of P was lower than for H. The percentage of CD4+/CD8+ PD1 and CD8+ PDL1 was higher in the DP and DNP groups than in the H group; the percentage of CD8+ PDL1 was higher in the DP than P groups. Subgingival micro-organisms in periodontitis had a significant metabolic shift in terms of their signature metabolites. Butyrate metabolism and phenylalanine metabolism may play a role in the pathogenesis of periodontitis with/without T2DM. Specifically, biphenyl degradation, tryptophan metabolism, and the two-component system may play important roles in periodontitis with T2DM. Lastly, the network relationship among subgingival micro-organisms, metabolites, blood glucose level, and T lymphocyte immunity were unbalanced. This study identified the changes in the subgingival microbiome associated with periodontitis in T2DM, as well as the associated network between bacterial flora, metabolism dysbiosis, and immune regulation.
| S-EPMC9743466 | biostudies-literature
Project description:Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell-depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon-?, interleukin (IL)-12, IL-17 and IL-22 production as well as T-bet and receptor-related orphan receptor gamma t expression compared with mice treated with the isotype control antibody. In contrast, NK cell depletion significantly increased Treg in cell number and related transcription factor (Foxp3) expression. The opposite trends of changes of Th1/Th17 and Treg led to significant reduction in the Th1/Treg and Th17/Treg ratios. The data implicate that NK cells play an important role in host defence against chlamydial lung infection, mainly through maintaining Th1/Treg and Th17/Treg balance.
| S-EPMC4929289 | biostudies-literature
Project description:BackgroundSjögren's syndrome (SS) is a chronic, systemic autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. The disease severely affects the health and life of patients, and the treatment of SS has always been a clinical challenge and essentially palliative. Mesenchymal stem cells (MSCs) have been reported to exert immunomodulatory effects and as a potential novel therapeutic strategy for SS. Labial gland-derived MSCs (LGMSCs) are a population of resident stem cells in the labial gland, first isolated by our group. Exosomes released by MSCs contain a large variety of bioactive molecules and considered to function as an extension of MSCs.MethodsLGMSCs were isolated from patients who were needed surgery to remove the lip mucocele and LGMSCs derived exosomes (LGMSC-Exos) were isolated by ultracentrifugation. The non-obese diabetic (NOD) mice were treated with LGMSCs or LGMSC-Exos by tail vein injection. The saliva flow rate of mice was determined and salivary glands were dissected and stained with hematoxylin and eosin. In vitro, peripheral blood mononuclear cells (PBMCs) from SS patients were cocultured with LGMSCs or LGMSC-Exos. Percentage of T helper 17 (Th17) cells and regulatory T (Treg) cells were determined by flow cytometry. The serum levels of cytokines in NOD mice and in the supernatant of the co-culture system by ELISA.ResultsTreatment with LGMSCs or LGMSC-Exos reduced inflammatory infiltration in the salivary glands, and restored salivary gland secretory function in NOD mice. Importantly, LGMSCs or LGMSC-Exos were demonstrated to inhibit the differentiation of Th17 cells but promote the induction of Treg cells in NOD mice and PBMCs from SS patients in vitro, accompanied by reduced interleukin 17 (IL-17), interferon gamma, and IL-6 levels and enhanced transforming growth factor beta and IL-10 secretion by T cells.ConclusionsLGMSCs are potential candidates for MSCs-based therapy and LGMSC-Exos might be utilized for establishing a new cell-free therapy against SS.
| S-EPMC8390194 | biostudies-literature
Project description:Periodontitis (PD) is a common dysbiotic inflammatory disease that leads to local bone deterioration and tooth loss. PD patients experience low-grade bacteremias with oral microbes implicated in the risk of heart disease, cancer, and kidney failure. Although Th17 effectors are vital to fighting infection, functional imbalance of Th17 effectors and regulatory T cells (Tregs) promote inflammatory diseases. In this study, we investigated, in a small pilot randomized clinical trial, whether expansion of inflammatory blood myeloid dendritic cells (DCs) and conversion of Tregs to Th17 cells could be modulated with antibiotics (AB) as part of initial therapy in PD patients. PD patients were randomly assigned to either 7 d of peroral metronidazole/amoxicillin AB treatment or no AB, along with standard care debridement and chlorhexidine mouthwash. 16s ribosomal RNA analysis of keystone pathogen Porphyromonas gingivalis and its consortium members Fusobacterium nucleatum and Streptococcus gordonii confirmed the presence of all three species in the reservoirs (subgingival pockets and blood DCs) of PD patients before treatment. Of the three species, P. gingivalis was reduced in both reservoirs 4-6 wk after therapy. Further, the frequency of CD1C+CCR6+ myeloid DCs and IL-1R1 expression on IL-17A+FOXP3+CD4+ T cells in PD patients were reduced to healthy control levels. The latter led to decreased IL-1β-stimulated Treg plasticity in PD patients and improvement in clinical measures of PD. Overall, we identified an important, albeit short-term, beneficial role of AB therapy in reducing inflammatory DCs and Treg-Th17 plasticity in humans with PD.
| S-EPMC6857811 | biostudies-literature
Project description:BackgroundGastrosphere, an enriched cellular population with stem-like properties believed to be responsible for an escape from immune-mediated destruction. Th17 and Treg cells play a major role in gastric cancer; however, their interaction with gastrospheres remained elusive.MethodPeripheral blood mononuclear cells were isolated from healthy donors and were cultured with conditioned media of MKN-45 (parental) cells as well as gastrospheres' conditioned media in the context of mixed lymphocyte reaction and in the presence of anti-CD3/CD28 beads. The proliferation was evaluated using CFSE staining; the percentages of CD4+CD25+FoxP3+ Treg and CD4+IL-17+ Th17 cells and IFN-γ+cells and the production of IL-17, TGF-β, and IL-10 were assessed by flow cytometry and ELISA, respectively. Finally, the cytotoxic potential of induced immune cells was measured by examining the secretion of lactate dehydrogenase from target cells.ResultsThe results revealed a decreased expansion of PBMCs postexposure to gastrospheres' conditioned medium which was concomitant with an increased percentage of Th17 and an enhanced Th17 to Treg ratio. The conditioned media of gastrospheres enhanced the secretion of IL-10 and IL-17 and decreased TGF-β. Interestingly, immune cells induced by gastrospheres showed significant cytotoxicity in terms of producing IFN-γ and death induction in target cells. All these changes were related to the upregulation of IL-6, IL-10, and IL-22 in gastrospheres compared to parental cells.ConclusionOur study showed that the condition media of gastrospheres can potentially induce Th17 with increasing in their cytotoxic effect. Based on our knowledge, the present study is the first study that emphasizes the role of gastrospheres in the induction of antitumor Th17 cells. However, it should be confirmed with complementary studies in vivo.
| S-EPMC7775146 | biostudies-literature
Project description:Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor ? (TGF?) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA).CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry.Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice.These findings provide evidence that transferred TGF?-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.
| S-EPMC4364395 | biostudies-literature