Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE215457 | GEO | 2023/04/08
REPOSITORIES: GEO
Similar Datasets
Project description:Allergic contact dermatitis (ACD) is a type IV hypersensitivity mainly mediated by Th1/Th17 immune response. Topical corticosteroid is currently the first-line treatment for allergic contact dermatitis (ACD) and systemic administration of immunosuppressive drugs are used in patients with severe disseminated cases. However, increased risk of adverse effects has limited their use. Thus, the development of a novel immunosuppressant for ACD with low toxicity is a challenging issue. In this study, we began our study by using a murine contact hypersensitivity (CHS) model of ACD to examine the immunosuppressive effects of DYRK1B inhibition. We found that mice treated with a selective DYRK1B inhibitor show reduced ear inflammation. In addition, a significant reduction of Th1 and Th17 cells in the regional lymph node upon DYRK1B inhibition was observed by FACS analysis. Studies in vitro further revealed that DYRK1B inhibitor does not only suppressed Th1 and Th17 differentiation, but also promotes regulatory T cells (Treg) differentiation. Mechanistically, FOXO1 signaling was enhanced due to the suppression of FOXO1Ser329 phosphorylation in the presence of DYRK1B inhibitor. Therefore, these findings suggest that DYRK1B regulates CD4 T cell differentiation through FOXO1 phosphorylation and DYRK1B inhibitor has a potential as a novel agent for treatment of ACD.
| S-EPMC10148813 | biostudies-literature
Project description:Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response
| PRJNA890299 | ENA
Project description:The cytokine IL-9, derived primarily from T-helper 9 (Th9) lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also has a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch-test sites from non-atopic patients were assayed using quantitative PCR and immunohistochemistry. The cytokines IFN-γ, IL-4, IL-17A, IL-9, and PU.1, a Th9 associated transcription factor, were elevated when compared with paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+ CD3+ and PU.1+ CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. Peripheral blood mononuclear cells from nickel-allergic patients, but not nonallergic controls, show significant IL-9 production in response to nickel. Blocking studies with mAbs to HLA-DR (but not HLA-A, -B, -C) or chloroquine significantly reduced this nickel-specific IL-9 production. In addition, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-γ production. A contact hypersensitivity model using IL-9(-/-) mice shows enhanced Th1 lymphocyte immune responses, when compared with wild-type mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD.
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Project description:Illuminating the mechanisms controlling glucose homeostasis may deepen our understanding of the pathogenesis of T2DM and provide new therapeutic strategies for T2DM in future. As reported, Dyrk1b is a pleiotropic protein and its genetic mutations associate with blood glucose levels. Yet, the role of Dyrk1b in glucose metabolism is not well understood. Herein, we find that hepatic Dyrk1b overexpression in mice impairs the glucose tolerance and insulin resistance, whereas global Dyrk1b deficiency improves glucose metabolism of mcie. Dyrk1b overexpression in vitro blunts insulin signalling and glucose uptake. Collectively, our study uncovers a novel link between hepatic Dyrk1b and whole body glucose homeostasis.
2025-05-29 | GSE234405 | GEO
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE263028 | GEO
Project description:One of the causes of hyperglycemia in type 2 diabetes is elevated hepatic glucose production. AKT-FOXO1 pathway is primarily involved in the hormonal upregulation of this process, and pharmacological or genetic inhibition of this pathway prevents diabetes in animal models. Here we report that DYRK1B regulates FoxO1 function through phosphorylation to regulate hepatic glucose metabolism. DYRK1B expression is induced by fasting and in diabetic mice. DYRK1B promoted hepatic gluconeogenesis and glucose intolerance in in vivo and in vitro model systems. Liver-specific DYRK1B conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacted with and phosphorylated FoxO1, primarily at T467S468, which is required for its nuclear localization. DYRK1B inhibited AKT mediated FoxO1 phosphorylation at T24 and S256 and enhanced its nuclear retention. DYRK1B mediated phosphorylation of FoxO1 enhanced the expression of gluconeogenic genes and promoted gluconeogenesis. Treatment with DYRK1B pharmacological inhibitor AZ191 significantly lowered blood glucose levels in diabetic mice. We conclude that DYRK1B is a regulator of glucose metabolism, and its pharmacological inhibition could serve as therapeutic target for treating diabetes.
2025-04-30 | GSE262106 | GEO
Project description:Illuminating the mechanisms controlling glucose homeostasis may deepen our understanding of the pathogenesis of T2DM and provide new therapeutic strategies for T2DM in future. As reported, Dyrk1b is a pleiotropic protein and its genetic mutations associate with blood glucose levels. Yet, its role in glucose metabolism remains to be established. Herein, we invetigate the role of Dyrk1b in glucose metabolism and the underlying mechanisms. We find that hepatic Dyrk1b overexpression in mice impairs the glucose tolerance and insulin resistance, whereas global Dyrk1b deficiency improves glucose metabolism of mcie. Dyrk1b overexpression in vitro blunts insulin signalling and glucose uptake. Quantitative proteomic analyses further reveal that Wbp2 is a putative target of Dyrk1b. Importantly, hepatic Wbp2 restoration rescues the glucose homeostasis in Dyrk1b overexpression mice. Additionally, ATAC-seq analyses indicate Dyrk1b’s role in remodelling hepatic chromatin landscape. Collectively, our study uncovers a novel link between hepatic Dyrk1b and whole body glucose homeostasis via modulation of hepatic Wbp2 expression.
2025-05-29 | GSE234275 | GEO
Project description:Here, we investigates the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure.We engineered DYRK1B transgenic and the effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis. In this dataset, we inquire the transcriptional profile of WT and DYRK1B transgenic hearts at 3-day and 8-week old.
2021-09-19 | GSE184155 | GEO
Project description: Not available
| S-EPMC9435531 | biostudies-literature