RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis.
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ABSTRACT:
SUBMITTER: Alvarez C
PROVIDER: S-EPMC8126725 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Histone deacetylases (HDACs) are important regulators of gene expression that are aberrantly regulated in several inflammatory and infectious diseases. HDAC inhibitors (HDACi) suppress inflammatory activation of various cell types through epigenetic and non-epigenetic mechanisms, and ameliorate pathology in a mouse model of periodontitis. Activation of gingival fibroblasts (GFs) significantly contributes to the development of periodontitis and the anaerobic bacterium Porphyromonas gingivalis plays a key role in driving chronic inflammation. Here, we analyzed the role of HDACs in inflammatory responses of GFs. Pan-HDACi suberoylanilide hydroxamic acid (SAHA) and/or ITF2357 (givinostat) significantly reduced TNFα- and P. gingivalis-inducible expression and/or production of a cluster of inflammatory mediators in healthy donor GFs (IL1B, CCL2, CCL5, CXCL10, COX2, and MMP3) without affecting cell viability. Selective inhibition of HDAC3/6, but not specific HDAC1, HDAC6, or HDAC8 inhibition, reproduced the suppressive effects of pan-HDACi on the inflammatory gene expression profile induced by TNFα and P. gingivalis, suggesting a critical role for HDAC3 in GF inflammatory activation. Consistently, silencing of HDAC3 expression with siRNA largely recapitulated the effects of HDAC3/6i on mRNA levels of inflammatory mediators in P. gingivalis-infected GFs. In contrast, P. gingivalis internalization and intracellular survival in GFs remained unaffected by HDACi. Activation of mitogen-activated protein kinases and NFκB signaling was unaffected by global or HDAC3/6-selective HDACi, and new protein synthesis was not required for gene suppression by HDACi. Finally, pan-HDACi and HDAC3/6i suppressed P. gingivalis-induced expression of IL1B, CCL2, CCL5, CXCL10, MMP1, and MMP3 in GFs from patients with periodontitis. Our results identify HDAC3 as an important regulator of inflammatory gene expression in GFs and suggest that therapeutic targeting of HDAC activity, in particular HDAC3, may be clinically beneficial in suppressing inflammation in periodontal disease.
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Project description:The most important microscopic characteristic of Cyclosporine A-induced gingival overgrowth is fibroepithelial hyperplasia.ObjectiveThe objective was to investigate the influence of previous exposure to Cyclosporine A over gingival epithelium in experimental periodontitis in rats.MethodsTwenty Wistar rats with 12 weeks-old were divided into four groups with 5 animals each: Control Group (CG); Cyclosporine Group (CsAG); Ligature group (LG) and Cyclosporine and Ligature Group (CsALG). Daily doses of CsA (10?mg/kg) were applied to CsAG and CsALG during 60 days since the beginning of the experiment and, a ligature was placed in LG and CsALG 30 days after the beginning of the experiment. After 60 days, animals were euthanized and gingival tissue was processed to histomorphometric analysis of epithelial thickness (mm2), immunohistochemical expression of PCNA (%) and inflammatory response. Data were analyzed by Kruskal-Wallis and Mann Whitney at 0.05 significance level.ResultsConsidering epithelial thickness, CG was thinner than all groups, CsALG was the largest and CsAG and LG were similar between each other. Regarding the PCNA expression CG (16.46 ± 9.26) was similar to CsAG (34.47 ± 19.75) and, LG (59.02 ± 10.33) was similar to CsALG (40.59 ± 18.25). Significant difference (p < 0.05) occurred only in inflammation presence comparing CG/LG and CsAG/CsALG. A weak positive correlation between the number of PCNA+ and inflammatory cells (p = 0.001; r = 0.611) was observed.ConclusionBased on these results it was concluded that the enlargement of gingival epithelium observed in experimental periodontitis can be increased by previous exposition to CsA and inflammatory conditions enhanced proliferative activity of the keratinocytes.
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Project description:Alpha-melanocyte stimulating hormone (α-MSH) is involved in normal skin wound healing and also has anti-inflammatory properties. The association of α-MSH to polyelectrolyte layers with various supports has been shown to improve these anti-inflammatory properties. This study aimed to evaluate the effects of nanofibrous membrane functionalized with α-MSH linked to polyelectrolyte layers on gingival cell inflammatory response. Human oral epithelial cells (EC) and fibroblasts (FB) were cultured on plastic or electrospun Poly-#-caprolactone (PCL) membranes with α-MSH covalently coupled to Poly-L-glutamic acid (PGA-α-MSH), for 6 to 24 h. Cells were incubated with or without Porphyromonas gingivalis lipopolysaccharide (Pg-LPS). Cell proliferation and migration were determined using AlamarBlue test and scratch assay. Expression of interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and transforming growth factor-beta (TGF-β) was evaluated using RT-qPCR method. Cell cultures on plastic showed that PGA-α-MSH reduced EC and FB migration and decreased IL-6 and TGF-β expression in Pg-LPS stimulated EC. PGA-α-MSH functionalized PCL membranes reduced proliferation of Pg-LPS stimulated EC and FB. A significant decrease of IL-6, TNF-α, and TGF-β expression was also observed in Pg-LPS stimulated EC and FB. This study showed that the functionalization of nanofibrous PCL membranes efficiently amplified the anti-inflammatory effect of PGA-α-MSH on gingival cells.
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Project description:Our previous study demonstrated that IL-10 secreting B (B10) cells alleviate inflammation and bone loss in experimental periodontitis. The purpose of this study is to determine whether antigen-specificity is required for the local infiltration of B10 cells. Experimental periodontitis was induced in the recipient mice by placement of silk ligature with or without the presence of live Porphyromonas gingivalis (P. gingivalis). Donor mice were pre-immunized by intraperitoneal (IP) injection of formalin-fixed P. gingivalis, or PBS as non-immunized control. Spleen B cells were purified and treated with LPS and CpG for 48 h to expand the B10 population in vitro. Fluorescence-labelled B10 cells were transferred into the recipient mice by tail vein injection and were tracked on day 0, 3, 5 and 10 using IVIS Spectrum in vivo imaging system. The number of B10 cells and P. gingivalis-binding B cells were significantly increased after in vitro treatment of LPS and CpG. On day 5, the fluorescence intensity in gingival tissues was the highest in mice transferred with B10 cells from pre-immunized donor mice. Gingival expression of IL-6, TNF-α, RANKL/OPG ratio and periodontal bone loss in recipient mice were significantly reduced, and the expression of IL-10 and the number of CD19+ B cells were significantly increased after pre-immunized B10 cell transfer in the presence of antigen, compared to those with non-immunized B10 cell transfer or no antigen presence. This study suggests that antigen specificity dictate the local infiltration of B10 cells into periodontal tissue and these antigen-specific B10 cells promote anti-inflammatory responses.
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Project description:The present study explored whether the dopamine 2-like receptor agonist, ropinirole, a drug used for treating Parkinson's disease, suppresses neutrophilic inflammation and alveolar bone loss in an experimental rat model of periodontitis. Periodontitis is a neutrophilic inflammatory disease caused by periodontal pathogens. An excessive T helper (Th)17 immune response is involved in the progression of periodontitis, and interleukin (IL)-17 promotes the exacerbation of inflammation and alveolar bone destruction. Recent evidence has suggested that dopamine signaling plays a key role in Th17 cell differentiation, and that dopamine 2-like receptor agonists suppress cytokine production from Th17 cells. We previously demonstrated that tannic acid, which is a dopamine 2-like receptor agonist, inhibits alveolar bone resorption in an experimental model of periodontitis. The present study used a carrageenan-induced rat model of periodontitis with or without ropinirole. Micro-computed tomography analysis was performed. Cells of the murine gingival epithelial cell line GE1 were stimulated with carrageenan and IL-17A in the presence or absence of ropinirole. The anti-inflammatory effect of ropinirole was analyzed using reverse transcription- quantitative PCR and enzyme-linked immunosorbent assay. Subsequently, in the carrageenan-induced rat model of periodontitis, alveolar bone resorption was observed in the maxillary second molar by micro-computed tomography analysis. Intriguingly, ropinirole suppressed the alveolar bone destruction. The expression levels of C-X-C motif chemokine ligand 1 (CXCL1) and IL-17 receptor A (IL-17RA) in GE1 cells were increased by carrageenan, and CXCL1 expression in GE1 cells was upregulated under IL-17A stimulation. Moreover, ropinirole inhibited CXCL1 and IL-17RA expression in GE1 cells in the presence of IL-17A and carrageenan. Finally, haloperidol promoted CXCL1 expression in GE1 cells in the presence of carrageenan. Overall, these findings suggested that ropinirole suppressed neutrophilic inflammation and alveolar bone destruction in periodontitis by inhibiting CXCL1 expression in gingival epithelial cells through the dopamine 2-like receptor. Thus, ropinirole shows promise as a drug for the treatment of periodontitis.
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