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A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [scRNA-seq]

ABSTRACT: A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.

ORGANISM(S): Mus musculus

PROVIDER: GSE296203 | GEO | 2025/06/12

REPOSITORIES: GEO

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A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [RNA-Seq]

Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.

2025-06-12 | GSE296201 | GEO

A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [ATAC-seq]

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A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [RNA-Seq]

Project description:A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [RNA-Seq]

| PRJNA1258204 | ENA

A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [scRNA-seq]

Project description:A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [scRNA-seq]

| PRJNA1258203 | ENA

A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [ATAC-seq]

Project description:A20’s Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis [ATAC-seq]

| PRJNA1258201 | ENA

Gene expression profile of human epidermal keratinocytes in response to IFNgamma, IL-4, IL-6, IL-17A and IL-22

Project description:To understand the role of epidermal keratinocytes in immunopathology of skin diseases with predominant T helper (Th) cell responses, we measured the genome-wide transcriptional profile of human keratinocytes in response to IFNgamma, IL-4, IL-17A or IL-22, major cytokines produced by Th1, Th2, Th17 or Th22 cells, respectively. IL-6 was also included in the transcriptional profile analysis because a variety of pro-inflammatory stimuli stimulate human keratinocytes to produce IL-6 that has an autocrine or paracrine role in epidermal immunity. We aimed to discover commonly expressed genes in human keratinocytes in response to pro-inflammatory cytokines, which would be associated with common pathophysiological responses in various skin diseases such as skin permeability barrier disruption or epidermal hyperplasia. Normal human keratinocytes (NHKs) were stimulated with IFNγ, IL-4, IL-6, IL-17A and IL-22 for 24 hours and harvested for total RNA extraction and hybridization on Affymetrix microarrays.

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The TNF family member TL1A induces IL-22 secretion in committed human TH17 cells via IL-9 induction

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2016-10-25 | GSE89133 | GEO

IL-22 Controls Iron-Dependent Nutritional Immunity Against Systemic Bacterial Infections

Project description:Host immunity limits iron availability to pathogenic bacteria, but whether immunity limits pathogenic bacteria from accessing host heme, the major source of iron in the body, remains unclear. Using Citrobacter rodentium, a mouse enteric pathogen and Escherichia coli, a major cause of sepsis in humans as models, we find that interleukin-22, a cytokine best known for its ability to promote epithelial barrier function, also suppresses the systemic growth of bacteria by limiting iron availability to the pathogen. Using an unbiased proteomic approach to understand the mechanistic basis of IL-22 dependent iron retention in the host, we have identified that IL-22 induces the production of the plasma hemoglobin scavenger haptoglobin and heme scavenger hemopexin. Moreover, the anti-microbial effect of IL-22 depends on the induction of hemopexin expression, while haptogloblin is dispensable. Impaired pathogen clearance in infected Il22-/- mice was restored by hemopexin administration and hemopexin-deficient mice had increased pathogen loads after infection. These studies reveal a previously unrecognized host defense mechanism regulated by IL-22 that relies on the induction of hemopexin to limit heme availability to bacteria leading to suppression of bacterial growth during systemic infections.

2017-02-03 | PXD005666 | Pride

Gene expression profile of human epidermal keratinocytes in response to IFNgamma, IL-4, IL-6, IL-17A and IL-22

2014-10-02 | GSE53751 | GEO

Gene expression of Listeria monocytogenes-infected HepG2 hepatocellular carcinoma in the presense of IL-17Aand IL-22

Project description:IL-17A and IL-22 induced several inflammation-induced genes and anti-microbial molecules including Pla2g2a and Lcn2 on HepG2 cells when the cells were treated with the cytokines before Listeria monocytogenes infection. HepG2 cells were treated with 50 ng/ml IL-17A and 10 ng/ml IL-22 before L. monocytogenes in vitro infection at MOI 10. Reference cells were not treated with the cytokines before the infection. Two independent experiments were carried out.

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