Different fibroblast subtypes propel spatially defined ileal inflammation through TNFR1 signalling in murine ileitis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1074727 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27919039.fastq.gz | Fastqsanger.gz | |||
| SRR27919040.fastq.gz | Fastqsanger.gz | |||
| SRR27919041.fastq.gz | Fastqsanger.gz | |||
| SRR27919042.fastq.gz | Fastqsanger.gz | |||
| SRR27919043.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 44 |
Similar Datasets
Project description:TNFΔΑRE mice represent a model for Crohn's Disease (CD) ileitis. We wanted to examine the cellular and trascriptional heterogeneity of immune and stroma cells (not including the epithelium) in the ileum of wild type and TNFΔΑRE mice.
2025-02-11 | GSE255350 | GEO
Project description:We have compared mRNA expression in full-thickness mouse colon between wildtype mice and mice with a genetic deletion in tumor necrosis factor receptor 1 (TNFR1, encoded by the Tnfrsf1a gene). This experiment was motivated by our observation that Il10-/- Tnfr1-/- double-knockout mice develop very-early-onset colitis at the time of weaning, significantly earlier than disease onset in Il10-/- single-knockout mice. This suggests that TNFR1 mediates protection from colitis. To understand these protective mechanisms at the transcript level in a non-inflammatory context, we performed transcriptome profiling (mRNA-Seq) on colons from 12-week-old Tnfr1-/- mice, which do not develop colitis, and wildtype littermates. These experiments revealed that an estimated 510 transcripts were upregulated and 377 downregulated in colonic tissue of Tnfr1-/- mice. We aggregated the transcript information to calculate gene expression and performed gene set enrichment analysis to identify signaling pathways altered in Tnfr1-/- mice. When queried against a high-confidence set of 50 signaling pathways, the Tnfr1-/- gene expression profile was associated with reduced mitosis and increased glycolysis, transforming growth factor beta signaling, DNA repair, and reactive oxygen species signaling. Gene ontological analysis classified some of the differentially expressed genes into cytokines, junctional proteins, and transcription factors, but within these groups there was no consensus on the direction of regulation. We also examined how differentially expressed transcripts (called the TNFR1-regulated transcriptome) compared to differentially expressed colonic transcripts from previously collected Tnfr2-/- animals (or the TNFR2-regulated transcriptome, available at the NCBI Gene Expression Omnibus under the accession GSE65408). The raw data were re-analyzed with the current pipeline to enable comparison. There was almost no correlation between TNFR1- and TNFR2-regulated transcripts. Only 30 (~3%) TNFR1-regulated transcripts were also TNFR2-regulated transcripts, and ~4% of the TNFR2-regulated genes were also TNFR1-regulated genes. Of the few co-regulated transcripts, there was a significant negative correlation in their direction of regulation in Tnfr1-/- versus Tnfr2-/- colons. Collectively these results indicate that TNFR1 and TNFR2 have mostly different and opposing effects on gene expression in the mouse colon. MANUSCRIPT ABSTRACT: BACKGROUND & AIMS: Very-early-onset inflammatory bowel disease (VEO-IBD) is a devastating disease beginning in early childhood, refractory to anti-tumor necrosis factor (anti-TNF) therapies, and associated with mutations in the interleukin 10 (IL-10) pathway. Contrary to mainstream clinical practice, cellular and animal studies have shown beneficial roles of TNF signaling in colitis, but how these roles are encoded through TNF’s receptors remains unknown. Here we examined the role of TNF receptor 1 (TNFR1, or p55) in modulating the onset and severity of colitis in the interleukin 10 (IL-10)-deficient mouse model. METHODS: Colitis severity was compared between Il10-/- Tnfr1-/- and Il10-/-- littermate mice at 2-12 weeks of age. To assess dysbiosis as a potential pathogenic mechanism, Il10-/- Tnfr1-/- mice were treated with neomycin and metronidazole and their cecal contents analyzed by 16S rRNA sequencing. Gene expression, barrier function, and epithelial proliferation and apoptosis were examined in adult colitis-free Tnfr1-/- wildtype littermates. RESULTS: In contrast to relatively healthy Il10-/- mice, Il10-/- Tnfr1-/- mice developed severe, antibiotic-treatable colitis shortly after weaning. Microbiotal composition was similar between Il10‑/- Tnfr1-/- mice and Il10-/- littermate controls. Tnfr1-/- mice expressed transcripts associated with reactive oxygen species and DNA repair pathways. Tnfr1-/- mice exhibited focal areas of crypt branching, higher colonic epithelial permeability, and hallmarks of DNA damage. CONCLUSIONS: TNFR1 promotes epithelial homeostasis and regulates commensal exposure. The lack of TNFR1 accelerates the onset and severity of IBD in the absence of tolerogenic signaling (i.e., lack of IL-10). Il10-/- Tnfr1-/- mice may serve as a valuable model of very-early-onset IBD (VEO-IBD).
2019-03-15 | GSE107933 | GEO
Project description:Athough anti-TNF therapies can be used to treat colitis associated with inflammatory bowel disease, in mice the loss of the TNF receptor TNFR1 (Tnfrsf1a) in the Il10-/- spontaneous colitis background results in acceleration of disease onset. Whereas Il10-/- mice on the Bl/6 background are relatively protected from colitis throughout life, Il10-/- Tnfr1-/- mice develop colitis beginning at 4 wks of age. Their disease results in nearly 50% mortality by 12 wks of age. Strikingly, Tnfr1-/- mice (with functional IL-10) exhibit evidence of mucosal dysfunction at 4 and 12 wks of age. These mucosal abnormalities include loss of barrier integrity, increased epithelial cell proliferation, crypt malformations, and increased immune cell infiltrate. Because of the early onset of mucosal abnormalities in Tnfr1-/- mice, with or without IL-10 expression, we hypothesized that TNFR1 plays important roles in colonic mucosal function in early life, prior to weaning. To test this hypothesis, we profiled, using mRNA-Seq, the colonic transcriptomes from wildtype and Tnfr1-/- mice at 2 wks of age. The results demonstrate that Tnfr1-/- mice have important gene expression changes, including reduced expression of Il1b, a marker of the proinflammatory "weaning reaction" that is required for establishment of mucosal tolerance in later life. TNFR1 therefore has key roles in colonic mucosal homeostasis in early life.
2020-08-05 | GSE155654 | GEO
Project description:The spatial organization of gut microbiome is essential for their interactions with the host. Recently, microbiota alteration in ileum is getting the increasing recognition due to the close interplay with inflammatory diseases and the tumor immunosurveillance. However, how ileal microbiome is spatially regulated remains unclear. Here, we show that DNA-damaging chemotherapy specifically remodels microbiota in ileal mucosa, resulting in the overgrowth of local family Lachnospiraceae that promotes antitumor immunity and synergizes with immune checkpoint blockage. Mechanistically, the prominent proliferative state of transit amplifying cells (TACs) in the ileal crypt presents a vulnerability to chemotherapy-caused genomic stress, resulting in the accumulation of cytosolic dsDNA that subsequently activates AIM2 inflammasome. AIM2-dependent production of IL18 boosts Th1 immunity in ileal lamina propria, which further impairs the antimicrobial host defense of proximal Paneth cells via activating IFN-γ-JAK-STAT signaling. Our findings demonstrate that AIM2 inflammasome shapes ileal microbiome via governing the compartmentalized cellular interplay in ileal crypt, providing mechanistic insights into the regulation of gut biogeography and implicating therapeutic strategies of spatial microbiome intervention using chemotherapy.
2024-03-12 | GSE168793 | GEO
Project description:The loss of TNFR1 (Tnfrsf1a) in the Il10-/- spontaneous mouse colitis background results in acceleration of disease onset. Whereas Il10-/- mice on the Bl/6 background are relatively protected from colitis throughout life, Il10-/- Tnfr1-/- mice develop colitis beginning at 4 wks of age. Their disease results in nearly 50% mortality by 12 wks of age. We hypothesized that this early-onset colitis was due to dysregulation of immune signals in early life, defining a key period known as the "weaning reaction" in which proinflammatory signals help induce mucosal tolerance of the microbiome. To test this hypothesis, we profiled, using mRNA-Seq, the colonic transcriptomes from Il10-/- and Il10-/- Tnfr1-/- mice at 2 wks of age. The results presented here show that Il10-/- Tnfr1-/- mice have reduced expression of cytokines at this early age, suggesting that they cannot amount an appropriate immune response. Thus, TNFR1 plays an important role in the weaning reaction and the acquisition of tolerance.
2020-08-04 | GSE155626 | GEO
Project description:Human colon carcinoma cells SKCO1 were deprived of either beta-catenin alone or beta-catenin together with TNFR1 and changes in mRNA levels were examined before and after TNFR1 ablation SKCO1 cells were transfected with either beta-catenin-specific siRNA alone or beta-catenin-specific siRNA together with a TNFR1-specific siRNA and changes in mRNA levels were examined before and after TNFR1 ablation
2014-10-02 | E-GEOD-61961 | biostudies-arrayexpress
Project description:Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-ĸB essential modulator in hepatocytes (NemoΔhepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoΔhepa mice. Therefore, we generated NemoΔhepa/TRAIL-/- and NemoΔhepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoΔhepa/TRAIL-/- displayed a similar phenotype to NemoΔhepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoΔhepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoΔhepa and NemoΔhepa/TRAIL-/- mice while NemoΔhepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoΔhepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice. Expression profiling of livers from wild type, NEMO, NEMO-TRIAL, and NEMO-TNFR null mice
2014-09-03 | E-GEOD-33161 | biostudies-arrayexpress
Project description:Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-ĸB essential modulator in hepatocytes (NemoΔhepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in NemoΔhepa mice. Therefore, we generated NemoΔhepa/TRAIL-/- and NemoΔhepa/TNFR1-/- animals and analyzed the progression of liver injury. NemoΔhepa/TRAIL-/- displayed a similar phenotype to NemoΔhepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in NemoΔhepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in NemoΔhepa and NemoΔhepa/TRAIL-/- mice while NemoΔhepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in NemoΔhepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice.
2014-09-03 | GSE33161 | GEO
Project description:Based on genetic risk factors and natural history, Crohn’s disease (CD) can be separated in two entities, an ileal and a colonic disease. Protein based-approaches are needed to elucidate whether such subphenotypes are related to distinct pathophysiological processes. In this work, we compared the proteome of ulcer edge to the one of paired control tissue in ileum and colon of CD patients. We revealed that ileal and colonic ulcer edge can be distinguished by a differential distribution of epithelial–mesenchymal transition proteins, neutrophil degranulation proteins and ribosomal proteins. In ileal and colonic ulcer edge, we found a quasi-systematic increase of the proteins implicated in the pathway of protein processing in endoplasmic reticulum and a quasi-systematic decrease of mitochondrial proteins. Our study provides for the first time protein-based evidences showing partly distinct pathophysiological processes associated to ileal and colonic ulcer edge in CD. This could constitute a first step toward the development of gut segment-specific diagnostic markers and therapeutics.
2019-07-15 | PXD012284 | Pride