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GSE71343
Mus musculus
15 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Notch receptors direct the differentiation of T helper (Th) cell subsets, but their influence on regulatory T (TR) cell responses is obscure. Interruption of Notch signaling in TR cells resulted in a super-regulatory phenotype, with suppression of TR cell Th1 programming and apoptosis as well as Th1 cell responses in systemic inflammation. In contrast, gain of function Notch1 signaling in TR cells resulted in lymphoproliferation, dysregulated Th1 responses and autoimmunity. To determine mechanisms by which Notch signaling may alter TR cell function, we compared the transcriptional profiles of splenic TR cells of Foxp3EGFPCre mice with those of Foxp3EGFPCreR26N1c/N1c (gain of function Notch signaling), Foxp3EGFPCreRBPJ/ (loss of function canonical Notch signaling), and Foxp3EGFPCreR26N1c/N1cRBPJ/ mice (gain of function/canonical loss of function Notch signaling).
Publication Title
Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
Illumina HiSeq 3000
Description
Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4Ra-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4Ra-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4Ra-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4Ra-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6Ra or the master TH17 cell regulator Retinoid-related Orphan Receptor ?t (ROR?t), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4Ra--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6–Foxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6– WT and CCR6– Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6–Foxp3EGFP+ Treg cells from same animals. Overall design: Three CCR6+Foxp3EGFP+ Il4raR576 replicates and four CCR6–Foxp3EGFP+ Il4raR576 Treg replicates (controls) were sampled
Publication Title
An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells.
Sample Metadata Fields
Sex, Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
To analyze gene expression in in regulatory T cell precursors that develop in the absence of a functional Foxp3 protein as compared to that of normal regulatory T cells
Publication Title
Regulatory T cell development in the absence of functional Foxp3.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Identification of an interleukin 13-induced epigenetic signature in allergic airway inflammation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Asthma is a common chronic inflammatory airway condition with a strong genetic and inheritability component, as siblings and first-degree relatives of those with the disease are often affected.
Publication Title
Identification of an interleukin 13-induced epigenetic signature in allergic airway inflammation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The relative contribution of polarized macrophages to the maintenance of tolerance is unknown. We examined their roles by in vivo adoptive transfer immunotherapy of M0, M1 and M2a macrophages as pre-treatment of colitis. In other experiments, M2a macrophages were used as pre-treatment or treatment of established colitis followed by immunotherapy with nTreg cells. Survival, weight gain, tissue infiltration, iTreg and Th17 cell development, T cell activation, and the frequency of proinflammatory cytokines were used as outcome measurements. Pre-treatment with M2a but not M1 macrophages increased the development of iTreg and Th17 cells. M2a macrophages used as pre-treatment or in treatment of established colitis allowed for successful therapy with nTreg cells.
Publication Title
Alternatively Activated Macrophages Boost Induced Regulatory T and Th17 Cell Responses during Immunotherapy for Colitis.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Induced Treg (iTreg) cells are essential for tolerance and can be used therapeutically, yet their stability in vivo and mechanisms of suppression are unresolved. Here, we used a treatment model of colitis to examine the role of autologous IL-10 in iTreg cell function. Mice treated with IL-10+/+ iTreg cells in combination with IL-10/ natural Treg (nTreg) cells survived and gained weight, even though iTreg cells were numerically disadvantaged and comprised just ~20% of all Treg cells in treated mice. Notably, ~85% of the transferred iTreg cells lost Foxp3 expression (ex-iTreg) but retained a portion of the iTreg transcriptome which failed to limit their pathogenic potential. The TCR repertoires of iTreg and ex-iTreg cells exhibited almost no overlap, which indicates that the two populations are clonally unrelated and maintained by different selective pressures. These data demonstrate a potent and critical role for iTreg cell produced IL-10 that can supplant the IL-10 produced by nTreg cells and compensate for the inherent instability of the iTreg population.
Publication Title
IL-10 produced by induced regulatory T cells (iTregs) controls colitis and pathogenic ex-iTregs during immunotherapy.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 10 Downloadable Samples
- Illumina HiSeq 2000
Description
The study demontrates differences in the transcriptome ( both of protein coding transcripts and long non-coding RNAs) in the unilateral ureteric obstruction model of renal fibrosis. Overall design: Renal tissue was studied from animals undergoing sham operation (as controls) or right ureteric ligation. Animals were sacrificed 2 and 8 days following ligation and the right kidney tissue was examined.
Publication Title
Whole-transcriptome analysis of UUO mouse model of renal fibrosis reveals new molecular players in kidney diseases.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 29 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Polymorphisms in the interleukin-4 receptor chain (IL-4R) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4R has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target and tissue-specific manner to mediate heightened expression of a subset of IL-4 and IL-13responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rdependent signaling.
Publication Title
Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [probe set (exon) version (huex10st)
Description
Screening small molecules and drugs for activity to modulate alternative splicing, we found that amiloride, distinct from four other intracellular pH-affecting analogues, could normalize the splicing of BCL-X, HIPK3 and RON/MISTR1 transcripts in human hepatocellular carcinoma Huh-7 cells. To elucidate the underlying mechanisms, our proteomic analyses of amiloride-treated cells detected hypo-phosphorylation of splicing factor SF2/ASF and also decreased levels of SRp20 and two un-identified SR proteins. We further observed decreased phosphorylation of AKT, ERK1/2 and PP1, while increased phosphorylation of p38 and JNK, suggesting that amiloride treatment down-regulated kinases and up-regulated phosphatases in the signal pathways known to affect the splicing factor protein phosphorylation. The amiloride effects of splicing factor protein hypo-phosphorylation andnormalizedoncogenic RNA splicing were both abrogated by pre-treatment with a PP1 inhibitor. We then performed global exon array analysis of Huh-7 cells treated with amiloride for 24 hours. Using gene array chips (Affymetrix GeneChip Human Exon 1.0 ST Array of >518000 exons of 42974 genes) for exon array analysis (set parameters of correlation coefficient 0.7, splicing index -1.585 , and log2 ratio -1.585), we found that amiloride influenced the splicing patterns of 551 genes involving at least 584 exons, which included 495 known protein-coding genes involving 526 exons, many of which play key roles in functional networks of ion transport, extracellular matrix, cytoskeletons and genome maintenance. Cellular functional analyses revealed subsequent invasion and migration defects, cell cycle disruption, cytokinesis impairment, and lethal DNA degradation in amiloride-treated Huh-7 cells. This study thus provides mechanistic underpinnings for exploiting small molecule modulation of abnormal RNA splicing for cancer therapeutics.
Publication Title
Small molecule amiloride modulates oncogenic RNA alternative splicing to devitalize human cancer cells.
Sample Metadata Fields
Cell line
View Samples