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The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation

ABSTRACT: The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation

PROVIDER: PRJNA636293 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11888100.fastq.gz	Fastqsanger.gz
	SRR11888101.fastq.gz	Fastqsanger.gz
	SRR11888102.fastq.gz	Fastqsanger.gz
	SRR11888103.fastq.gz	Fastqsanger.gz
	SRR11888104.fastq.gz	Fastqsanger.gz

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Similar Datasets

The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation

Project description:Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.

2021-01-11 | GSE151533 | GEO

Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α -dependent pathways

Project description:In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and non-pathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis (EAE), an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase (ALK)4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances anti-inflammatory gene modules. Whole genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other anti-inflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1 and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a novel critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.

2020-03-06 | GSE146439 | GEO

activin A treated Th17 cells from mouse

Project description:Whole cell extracts from mouse Th17 cells treated with activin A were profiled with extensive fractionation and bottom-up proteomics

2020-05-18 | PXD017757 | Pride

Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α -dependent pathways

Project description:Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α -dependent pathways

| PRJNA610576 | ENA

Pathogenic TH17 cells utilize BHLHE40 to instruct myeloid cells during autoimmune neuroinflammation

Project description:Pathogenic TH17 cells utilize BHLHE40 to instruct myeloid cells during autoimmune neuroinflammation

| PRJNA982794 | ENA

Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α-dependent pathways.

Project description:In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.

| S-EPMC7275751 | biostudies-literature

Oligodendrocyte regulation during autoimmune neuroinflammation

Project description:Oligodendrocyte regulation during autoimmune neuroinflammation

| PRJNA755962 | ENA

Pathogenic TH17 cells utilize BHLHE40 to instruct myeloid cells during autoimmune neuroinflammation

Project description:TH17 cells are implicated in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). We previously reported that the transcription factor BHLHE40 marks cytokine-producing pathogenic TH cells during EAE, and that its expression in T cells is required for clinical disease. Here, using dual reporter mice, we show BHLHE40 expression within TH1/17 and ex-TH17 cells following EAE induction. Il17a-Cre-mediated deletion of BHLHE40 in TH cells led to less severe EAE with reduced TH cell cytokine production. Characterization of the leukocytes in the central nervous system during EAE by scRNA-sequencing identified differences in the infiltrating myeloid cells when BHLHE40 was present or absent in TH17 cells. Our studies highlight the importance of BHLHE40 in promoting TH17 cell encephalitogenicity and instructing myeloid cell responses during active EAE.

2023-11-01 | GSE234705 | GEO

Activin/Nodal signaling in mouse embryonic stem cells

Project description:Members of the transforming growth factor (TGF)-β superfamily play essential roles in the pluripotency, self-renewal, and differentiation of embryonic stem cells. While bone morphogenic proteins maintain pluripotency of undifferentiated mouse ES cells, the role of Activin/Nodal signaling is less clear. To determine the target genes of Activin/Nodal-Smad2 signaling in undifferentiated embryonic stem cells, changes in gene expression were examined following stimulation with recombinant Activin (2 hours) or after inhibition of Activin/Nodal with SB431542 (24 hours) using defined media culture conditions with LIF and 20 ng/mL BMP4. SB431542 is a specific inhibitor of ALK4/5/7 receptors and antagonizes both Activin and Nodal signaling. Via western analysis, Activin stimulation increased pSmad2 in ES cells after 2 hours, and treatment with SB431542 for 24 hours virtually eliminated pSmad2. Total Smad2 expression remained unchanged through these manipulations. RNA from cells treated with Activin or SB431542 was extracted by standard methods with Qiagen RNeasy columns. The RNA was analyzed with the Mouse Genome 430A Array from Affymetrix. Samples were performed in duplicate, and RNA from cells treated with Activin or SB431542 was compared to untreated embryonic stem cells.

2009-08-31 | GSE17879 | GEO

Oligodendrocyte regulation during autoimmune neuroinflammation

Project description:The present study had the purpose to analyze the transcriptional state of oligodendrocytes in an animal model of multiple scleroris resembling autoimmune neuroinflammation and compared with control mice treated with ovalbumin. The results revealed that oligodendrocytes from the EAE (experimental autoimmune encephalomyelitis) model upregulate genes that are involved in immune processes providing evidence that oligodendrocytes can develop an immune phenotype in particular neuroinflammatory conditions.

2021-08-21 | GSE182341 | GEO

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