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The novel RNA binding protein IMP2 drives a stromal-Th17 cell inflammatory circuit in autoimmune neuroinflammation

ABSTRACT: The novel RNA binding protein IMP2 drives a stromal-Th17 cell inflammatory circuit in autoimmune neuroinflammation

PROVIDER: PRJNA748707 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15207988_1.fastq.gz	Fastqsanger.gz
	SRR15207988_2.fastq.gz	Fastqsanger.gz
	SRR15207989_1.fastq.gz	Fastqsanger.gz
	SRR15207989_2.fastq.gz	Fastqsanger.gz
	SRR15207990_1.fastq.gz	Fastqsanger.gz

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The novel RNA binding protein IMP2 drives a stromal-Th17 cell inflammatory circuit in autoimmune neuroinflammation

Project description:Posttranscriptional control of Ccl2 in stromal cells by IMP2 is required to permit IL-17-driven progression of EAE pathogenesis. Using an optimized data analysis workflow, we mapped about 40 million sequence reads per sample to the mouse genome (build mm10) and identified potential differentially regulated transcripts in the lymph nodes of EAE Imp2 KO mice (n=3) compared to EAE WT mice (n=3) with an absolute fold change ≥1.5, p value <0.05 and RPKM in WT mice >1. Altered expression of potential genes was confirmed with qRT–PCR.

2021-07-23 | GSE180561 | GEO

The RNA-binding protein IMP2 drives a stromal-Th17 cell circuit in autoimmune neuroinflammation.

Project description:Stromal cells are emerging as key drivers of autoimmunity, partially because they produce inflammatory chemokines that orchestrate inflammation. Chemokine expression is regulated transcriptionally but also through posttranscriptional mechanisms, the specific drivers of which are still incompletely defined. CCL2 (MCP1) is a multifunctional chemokine that drives myeloid cell recruitment. During experimental autoimmune encephalomyelitis (EAE), an IL-17-driven model of multiple sclerosis, CCL2 produced by lymph node (LN) stromal cells was essential for immunopathology. Here, we showed that Ccl2 mRNA upregulation in human stromal fibroblasts in response to IL-17 required the RNA-binding protein IGF-2 mRNA-binding protein 2 (IGF2BP2, IMP2), which is expressed almost exclusively in nonhematopoietic cells. IMP2 binds directly to CCL2 mRNA, markedly extending its transcript half-life, and is thus required for efficient CCL2 secretion. Consistent with this, Imp2-/- mice showed reduced CCL2 production in LNs during EAE, causing impairments in monocyte recruitment and Th17 cell polarization. Imp2-/- mice were fully protected from CNS inflammation. Moreover, deletion of IMP2 after EAE onset was sufficient to mitigate disease severity. These data showed that posttranscriptional control of Ccl2 in stromal cells by IMP2 was required to permit IL-17-driven progression of EAE pathogenesis.

| S-EPMC8855811 | biostudies-literature

The m6A reader IMP2 directs autoimmune inflammation through an IL-17- and TNFa-dependent C/EBP transcription factor axis

Project description:Using IMP2-deficient mice to study the role of the RNA-binding protein (RBP) IMP2 in models of autoimmunity, namely autoimmune glomerulonephritis

2021-07-02 | GSE178710 | GEO

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

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Oligodendrocyte regulation during autoimmune neuroinflammation

Project description:Oligodendrocyte regulation during autoimmune neuroinflammation

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Tetramerization of Transcription Factor STAT5 in Monocytes Promotes Autoimmune-mediated Neuroinflammation via the Regulation of CCL17

Project description:STAT5 plays a critical role in mediating cellular responses following cytokine stimulation. The activated STAT5 proteins can form dimers and tetramers with distinct biological functions. The role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic Th17 cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrated that STAT5 tetramerization regulates the GM-CSF-dependent production of CCL17 by MDCs. Importantly, DKI Th17 cells expanded with CCL17 exhibit more severe EAE. Mechanistically, the effect of CCL17 is dependent on the activity of the integrin VLA-4. Thus, our study uncovered a novel GM-CSF-STAT5 tetramer-CCL17 pathway that promotes autoimmune neuroinflammation via the regulation of Th17 cell migration.

2021-11-30 | GSE181924 | GEO

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-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

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

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

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