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The Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells

ABSTRACT: The Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells

PROVIDER: PRJNA527095 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8729101_1.fastq.gz	Fastqsanger.gz
	SRR8729101_2.fastq.gz	Fastqsanger.gz
	SRR8729102_1.fastq.gz	Fastqsanger.gz
	SRR8729102_2.fastq.gz	Fastqsanger.gz
	SRR8729103_1.fastq.gz	Fastqsanger.gz

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The Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells

Project description:CD4 T cells were treated with DMSO (control) or FGIN-1-27 under Th17 polarizing conditions and RNA sequencing was done to look at differentially expressed transcripts

2020-03-09 | GSE128308 | GEO

Anxiolytic Drug FGIN-1-27 Ameliorates Autoimmunity by Metabolic Reprogramming of Pathogenic Th17 Cells.

Project description:Th17 cells are critical drivers of autoimmune diseases and immunopathology. There is an unmet need to develop therapies targeting pathogenic Th17 cells for the treatment of autoimmune disorders. Here, we report that anxiolytic FGIN-1-27 inhibits differentiation and pathogenicity of Th17 cells in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model of Th17 cell-driven pathology. Remarkably, we found that the effects of FGIN-1-27 were independent of translocator protein (TSPO), the reported target for this small molecule, and instead were driven by a metabolic switch in Th17 cells that led to the induction of the amino acid starvation response and altered cellular fatty acid composition. Our findings suggest that the small molecule FGIN-1-27 can be re-purposed to relieve autoimmunity by metabolic reprogramming of pathogenic Th17 cells.

| S-EPMC7048748 | biostudies-literature

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity

Project description:Regulatory T cells (Treg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH17 cell) immunity. Selectively increased intestinal TH17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

2023-08-08 | GSE217949 | GEO

REV-ERBa regulates TH17 cell development and autoimmunity

Project description:RORγt is well recognized as the lineage defining transcription factor for TH17 cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here we demonstrate that the transcriptional repressor REV-ERBa is exclusively expressed in TH17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as RORγt-dependent, including Il17a. Deletion of REV-ERBa enhanced TH17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed TH17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBa negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases.

2018-12-19 | GSE122726 | GEO

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity [scRNA-Seq]

Project description:Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

2023-08-08 | GSE217947 | GEO

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity [RNA-Seq]

2023-08-08 | GSE189321 | GEO

REV-ERBa regulates TH17 cell development and autoimmunity

Project description:REV-ERBa regulates TH17 cell development and autoimmunity

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Activation of gp130 signaling in T-cells drives TH17-mediated multi-organ autoimmunity

Project description:Purpose: Recently discovered activating Interleukin-6 receptor subunit beta (IL6ST, encoding glycoprotein 130 (gp130)) mutations, as well as germline Signal transducer and activator of transcription 3 (STAT3) gain-of-function mutations are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis, resulting in an unmet medical need. Methods: To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, in this study we constitutively activated the gp130/JAK/STAT3 axis by means of a transgene, L-gp130, specifically targeted to T-cells. Results: Activating gp130 signaling in vivo resulted in fatal early-onset multi-organ autoimmunity, resembling numerous clinical features of human STAT3 gain-of-function disease. We observed strong T-cell activation and effector differentiation, accompanied by TH17 expansion and interferon-gamma production. Transcriptome profiling of murine CD4+ and CD8+ T-cells revealed commonly dysregulated genes and a STAT3 gain-of-function signature that was used to discriminate between STAT3 gain-of-function and healthy control patients. Conclusions: Hyperactive gp130/STAT3 signaling leads to strong TH17-mediated autoimmunity phenotypically resembling human STAT3 gain-of-function disease and identify TH17-cells as a key cellular subset for initiation and maintenance of autoimmunity

2023-10-01 | GSE198849 | GEO

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

Project description:Protein arginine methyltransferase 5 promotes cholesterol biosynthesis mediated Th17 responses and autoimmunity [Th17]

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Ezetimibe Ameliorates Ankylosing Spondylitis by Suppressing Th17 Differentiation

Project description:Ezetimibe Ameliorates Ankylosing Spondylitis by Suppressing Th17 Differentiation

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