Effect of Curcumin on Systemic T Helper 17 Cell Response; Gingival Expressions of Interleukin-17 and Retinoic Acid Receptor-Related Orphan Receptor γt; and Alveolar Bone Loss in Experimental Periodontitis

The resveratrol is a polyphenol known for its health benefits, which includes the ability to interfere in the osteoblastogenesis, which may foster adverse immunomodulators effects in the host response to periodontal disease. In the present study we evaluated the appearance of periodontal tissues of rats with experimentally induced periodontitis, by using resveratrol. Twenty-four male Wistar rats were used, in which half of the animals received a ligature around the first lower molars, then forming the groups with experimental periodontitis. Next, four groups were created: 1) Control Group (CON); 2) The Ligature Group (LIG); 3) Group Resveratrol (RSV); 4) Ligature-Resveratrol Group (LIG-RSV). The animals of the Resveratrol groups were daily dosed with 10 mg/kg of body weight of polyphenol orally, during four weeks. After 105 days of experimental period, euthanasia was performed. The results showed a significantly lower alveolar bone loss (p<0.05) in animals that received resveratrol, and still, the polyphenol was able to reduce concentration of interleukin 17 (IL-17) in the groups dosed with it. Our conclusion is that dosing rats with experimental periodontitis with resveratrol could cause a protective effect on the alveolar bone loss, in addition to act positively on the IL-17.

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The retinoic acid receptor drives neuroinflammation and fine tunes the homeostasis of interleukin-17-producing T cells

10.1101/2020.08.12.247510 ◽

2020 ◽

Author(s):

Rasmus Agerholm ◽

John Rizk ◽

Darshana Kadekar ◽

Annie Borch ◽

Sine Reker Hadrup ◽

...

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Cell Cycle Progression ◽

Retinoic Acid Receptor ◽

Γδ T Cells ◽

Interleukin 17 ◽

T Helper 17 ◽

Acid Receptor ◽

Expression Of Genes ◽

The Brain

AbstractThe vitamin A metabolite retinoic acid (RA) and its receptor (RAR) are one of the key interactions regulating cellular immunity and neural signaling. Whether endogenous RA-RAR interactions contribute to the development of neuroinflammation and diseases like multiple sclerosis, remains to be elucidated. Herein, we used the murine experimental autoimmune encephalomyelitis (EAE) model and an established genetic RAR silencing approach to decipher its role in pathogenic T cell responses. We show that RAR is necessary for the development of interleukin(IL)-17-driven, cell-mediated immunopathology in the brain and that it fine tunes the homeostasis of IL-17-producing gamma delta (γδT17) and CD4+ T cells (TH17). At steady-state, RAR was required in the γδT17 compartment to sustain optimal cell numbers and maintain expression of genes involved in cell cycle progression. In contrast, RAR negatively regulated T helper-17 (TH17) cell homeostasis. Our data show that RAR is required during the early phases of EAE in order to induce a γδT17 response and that its activity is necessary throughout the course of the disease to allow TH17 and γδT17 cells to infiltrate the brain. This is correlated with failure of RAR deficient cells to express surface integrin-alpha4, a major brain homing molecule. Collectively, our work demonstrates that endogenous RA-RAR interactions are important for the homeostasis of IL-17-producing T cells and necessary for their pathogenicity during neuroinflammation.One sentence summaryRetinoic acid receptor activity was required on IL-17-producing CD4+ and γδ T cells to induce their neuropathogenicity, and to regulate both positively and negatively their homeostasis.

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Periodontitis-mediated Conversion of CD4+CD25+ Regulatory T Cells into Proinflammatory Interleukin 17-producing T Helper Cells

10.21203/rs.3.rs-361398/v1 ◽

2021 ◽

Author(s):

Hongrui Liu ◽

Dongfang Li ◽

Minqi Li

Keyword(s):

Th17 Cell ◽

Alveolar Bone ◽

Treg Cells ◽

Inflammatory Factors ◽

Gingival Tissue ◽

Control Group ◽

Interleukin 17 ◽

Related Gene ◽

T Helper ◽

Experimental Periodontitis

Abstract Background: Among CD4+ T helper (Th) cells, Th17-Treg imbalance is a major pathogenesis of Chronic periodontitis (CP). Treg cells are often considered to play a protective role but they may have plasticity. This study aimed to clarify the regulatory role of Th17-Treg balance in periodontitis and further reveal Treg plasticity.Methods: An experimental periodontitis model was established by ligation of a silk thread and local injection of Pg-LPS. Inflammatory factors in serum and gingival tissues were measured by ELISA and RT-PCR. The degree of alveolar bone absorption was evaluated by micro-CT and histomorphological analysis. Quantities of Treg and Th17 cell and their related gene expression levels were examined. Furthermore, after magnetic bead-sorting spleen Treg cells, their characteristic genes and Th17 cell-related factors were explored at the mRNA level.Results: Inflammatory cytokines in serum and gingival tissue increased significantly in experimental periodontitis, which revealed obvious crestal bone loss around maxillary second molars. Consistently, we found increased secretion of RANKL by osteoblasts, thereby promoting the formation of osteoclasts and enhancing their activity in periodontitis. Further analysis showed that the number of Th17 cells and expression of related genes increased more significantly than Treg cells, demonstrating Treg-Th17 imbalance in periodontitis. Flow cytometry showed that the proportions of Treg cells in the blood and spleen of the periodontitis group was lower than those of the control group. Furthermore, Treg cell-related gene Foxp3 was downregulated and their expression of Th17 cell-related genes Rorc and IL-17A were increased. Conclusions: These results provided evidence that periodontitis may lead to Treg-Th17 conversion, although its mechanisms requires further study.

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In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells

Journal of Experimental Medicine ◽

10.1084/jem.20080034 ◽

2008 ◽

Vol 205 (6) ◽

pp. 1381-1393 ◽

Cited By ~ 368

Author(s):

Matthias Lochner ◽

Lucie Peduto ◽

Marie Cherrier ◽

Shinichiro Sawa ◽

Francina Langa ◽

...

Keyword(s):

T Cells ◽

Retinoic Acid Receptor ◽

Cell Receptor ◽

Nuclear Hormone Receptor ◽

Orphan Receptor ◽

T Helper ◽

T Helper 17 ◽

Infection And Inflammation ◽

And Function

The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt+ T cells express IL-17. We report here that RORγt+ Tαβ cells include Foxp3+ cells that coexist with IL-17–producing RORγt+ Tαβ cells in all tissues examined. The Foxp3+ RORγt+ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3+ to IL-17–producing RORγt+ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt+ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3+ RORγt+ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt+ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

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Delineation of the molecular determinants of the unique allosteric binding site of the orphan nuclear receptor RORγt

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013581 ◽

2020 ◽

Vol 295 (27) ◽

pp. 9183-9191

Author(s):

Iris A. Leijten-van de Gevel ◽

Luc Brunsveld

Keyword(s):

Drug Discovery ◽

Ligand Binding ◽

Autoimmune Diseases ◽

Retinoic Acid Receptor ◽

Binding Pocket ◽

Orphan Receptor ◽

Interleukin 17 ◽

Orphan Nuclear Receptor ◽

T Helper 17 ◽

Helix 12

Nuclear receptors (NRs) are high-interest targets in drug discovery because of their involvement in numerous biological processes and diseases. Classically, NRs are targeted via their hydrophobic, orthosteric pocket. Although successful, this approach comes with challenges, including off-target effects due to lack of selectivity. Allosteric modulation of NR activity constitutes a promising pharmacological strategy. The retinoic acid receptor-related orphan receptor-γt (RORγt) is a constitutively active NR that positively regulates the expression of interleukin-17 in T helper 17 cells. Inhibiting this process is an emerging strategy for managing autoimmune diseases. Recently, an allosteric binding pocket in the C-terminal region of the ligand-binding domain (LBD) of RORγt was discovered that is amenable to small-molecule drug discovery. Compounds binding this pocket induce a reorientation of helix 12, thereby preventing coactivator recruitment. Therefore, inverse agonists binding this site with high affinity are actively being pursued. To elucidate the pocket formation mechanism, verify the uniqueness of this pocket, and substantiate the relevance of targeting this site, here we identified the key characteristics of the RORγt allosteric region. We evaluated the effects of substitutions in the LBD on coactivator, orthosteric, and allosteric ligand binding. We found that two molecular elements unique to RORγt, the length of helix 11′ and a Gln-487 residue, are crucial for the formation of the allosteric pocket. The unique combination of elements present in RORγt suggests a high potential for subtype-selective targeting of this NR to more effectively treat patients with autoimmune diseases.

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