Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA391245 | ENA |
REPOSITORIES: ENA
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Project description:The Ras family of GTPases play an important role in signaling nodes downstream to T cell receptor and CD28 activation, potentially lowering the threshold for TCR activation by autoantigens. Somatic mutation in NRAS or KRAS may cause a rare autoimmune disorder coupled with abnormal expansion of lymphocytes. T cells from Rheumatoid Arthritis (RA) patients show excessive activation of Ras/MEK/ERK pathway. The small molecule farnesylthiosalicylic acid (FTS) interferes with the interaction between Ras GTPases and their prenyl-binding chaperones to inhibit proper plasma membrane localization. In the present study, we tested the therapeutic and immunomodulatory effects of FTS and its derivative 5-fluoro-FTS (F-FTS) in the rat adjuvant-induced arthritis model (AIA). We show that AIA severity was significantly reduced by oral FTS and F-FTS treatment compared to vehicle control treatment. FTS was as effective as the mainstay anti-rheumatic drug methotrexate, and combining the two drugs significantly increased efficacy compared to each drug alone. We also discovered that FTS therapy inhibited both the CFA-driven in vivo induction of Th17 and IL-17/IFN-g producing double positive as well as the upregulation of serum levels of the Th17-associated cytokines IL-17A and IL-22. By gene microarray analysis of effector CD4+ T cells from CFA-immunized rats, re-stimulated in vitro with the mycobacterium tuberculosis heat-shock protein 65 (Bhsp65), we determined that FTS abrogated the Bhsp65-induced transcription of a large list of genes (e.g. Il17a/f, Il22, Ifng, Csf2, Lta, and Il1a). The functional enrichment bioinformatics analysis showed significant overlap with predefined gene sets related to inflammation, immune system processes and autoimmunity. In Conclusions, FTS and F-FTS display broad immunomodulatory effects in AIA with inhibition of the Th17-type response to a dominant arthritogenic antigen. Hence, targeting Ras signal-transduction cascade is a potential novel therapeutic approach for RA.
2017-08-11 | GSE100280 | GEO
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
2022-10-25 | GSE163340 | GEO
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
2022-10-25 | GSE163339 | GEO
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
2022-10-25 | GSE163338 | GEO
Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.
2022-10-25 | GSE163341 | GEO
Project description:Non-canonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen
2020-07-01 | GSE151447 | GEO
Project description:It is well known that some pathogenic cells have enhanced glycolysis, the regulatory network leading to increased glycolysis are not well characterized. Here, we show that CNS-infiltrated pathogenic TH17 cells from diseased mice specifically upregulate glycolytic pathway genes compared to homeostatic intestinal TH17 cells. Bioenergetic assay and metabolomics analyses indicate that in vitro derived pathogenic TH17 cells are highly glycolytic compared to nonpathogenic TH17 cells. Chromatin landscape analyses demonstrate TH17 cells in vivo show distinct chromatin states, and pathogenic TH17 cells show enhanced chromatin accessibility at glycolytic genes with NF-kB binding sites. Mechanistic studies reveal that miR-21 targets the E3 ubiquitin ligase Peli1-c-Rel pathway to promote glucose metabolism of pathogenic TH17 cells. Therapeutic targeting c-Rel-mediated glycolysis in pathogenic TH17 cells represses autoimmune diseases. These findings extend our understanding of the regulation TH17 cell glycolysis in vivo and provide insights for future therapeutic intervention to TH17 cell mediated autoimmune diseases.
2020-04-01 | GSE127768 | GEO
Project description:The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. Here, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations like those found in human RA. Notably, murine macrophage subtypes like those in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNFa induced CD38+ macrophages that enhanced Th17 functionality. Murine synovial CD38+ macrophages were expanded during arthritis and their depletion or blockade via TNFa-neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNFa to drive inflammatory arthritis.
2022-01-05 | GSE184609 | GEO
Project description:Th17 cells can transdifferentiate into other T cell subsets in the context of infections or inflammatory conditions. In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis, however, there have been no attempts to target Th17 cell plasticity using vaccines. We aimed to change the phenotype of existing Th17 cells by a protein-in-adjuvant approach and found that antigen formulated in all-trans retinoic acid (ATRA)-containing cationic liposomes (CAF16) effectively inhibited existing Th17 responses. Strikingly, transcriptomic analysis of sorted Th17 cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In addition, vaccination with myelin-specific (MOG) antigen in CAF16 reduced Th17 responses and alleviated disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. This highlights CAF16 as a novel delivery system for ATRA with potential for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.
2024-02-27 | GSE240800 | GEO
Project description:Th17 cells can transdifferentiate into other T cell subsets in the context of infections or inflammatory conditions. In many autoimmune diseases, autoantigen-specific Th17 cells play a pivotal role in disease pathogenesis, however, there have been no attempts to target Th17 cell plasticity using vaccines. We aimed to change the phenotype of existing Th17 cells by a protein-in-adjuvant approach and found that antigen formulated in all-trans retinoic acid (ATRA)-containing cationic liposomes (CAF16) effectively inhibited existing Th17 responses. Strikingly, transcriptomic analysis of sorted Th17 cells from IL-17 fate reporter mice revealed a shift of antigen-specific Th17 cells to exTh17 cells, expressing functional markers associated with T cell regulation and tolerance. In addition, vaccination with myelin-specific (MOG) antigen in CAF16 reduced Th17 responses and alleviated disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. This highlights CAF16 as a novel delivery system for ATRA with potential for changing the phenotype of existing Th17 cells in the context of immune mediated diseases.
2024-02-27 | GSE240801 | GEO