The dual lipid desaturase/hydroxylase DEGS2 controls phytoceramide levels necessary to counter intestinal inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235544 | GEO | 2023/08/24
REPOSITORIES: GEO
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2022-10-25 | PXD029136 | Pride
Project description:In the DSS-induced colitis model, the epithelial damage and resulting inflammation is restricted to the colon, with a potential influence on the microbial composition in the adjacent cecum. Several studies have reported changes of the gut microbiota in the DSS-induced colitis model and other mouse models of IBD. Furthermore, metaproteomics analysis of the gut microbiome in a mouse model of Crohn’s disease demonstrated that disease severity and location are microbiota-dependent, with clear evidence for the causal role of bacterial dysbiosis in the development of chronic ileal inflammation. We have developed a refined model of chronic DSS-induced colitis that reflects typical symptoms of human IBD without a risky body weight loss usually observed in DSS models [Hoffmann et al., submitted]. In this study, we used metaproteomics to characterize the disease-related changes in bacterial protein abundance and function in the refined model of DSS-induced colitis. To assess the structural and functional changes, we applied 16S rRNA gene sequencing and metaproteomics analysis of the intestinal microbiota in three different entities of the intestinal environment, i.e. colon mucus, colon content and cecum content.
2020-03-17 | PXD007220 | Pride
Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).
2013-02-28 | E-GEOD-43416 | biostudies-arrayexpress
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2013-09-16 | E-GEOD-36056 | biostudies-arrayexpress
Project description:Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of inflammatory bowel disease (IBD) in which epigenetic modulations are pivotal elements. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, a histone H3K36 trimethyltransferase, maintains intestinal epithelial homeostasis under inflammatory conditions. GEO public database and IBD tissues were used to investigate the clinical relevance of SetD2 in IBD. To define the role of SetD2 in the colitis, we generated mice with epithelial-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. We isolated intestinal epithelial cells (IECs), performed RNA-seq and H3K36me3 ChIP-seq analysis to uncover the mechanism. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. SETD2 expression was decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice had abnormal loss of mucosa-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and promoted early intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice exhibited increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption. Intestinal permeability was markedly increased in Setd2Vil-KO mice. Setd2 ablation drived inflammation-associated CRC. Deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and the defects in barrier integrity. N-acetyl-l-cysteine (NAC) treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Moreover, overexpression of antioxidase PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. Deficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. More importantly, we show that Setd2 depletion results in excess ROS by directly down-regulating PRDX6, an antioxidant protein that inhibit excess ROS. Thus, our results highlight an epigenetic mechanism by which Setd2 mediates oxidative stress to modulate intestinal epithelial homeostasis.
2020-09-25 | GSE151967 | GEO
Project description:Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier disruption is one of the major causes of inflammatory bowel disease (IBD) in which epigenetic modulations are pivotal elements. However, the epigenetic mechanisms underlying the epithelial barrier integrity regulation remain largely unexplored. Here, we investigated how SETD2, a histone H3K36 trimethyltransferase, maintains intestinal epithelial homeostasis under inflammatory conditions. GEO public database and IBD tissues were used to investigate the clinical relevance of SetD2 in IBD. To define the role of SetD2 in the colitis, we generated mice with epithelial-specific deletion of Setd2 (Setd2Vil-KO mice). Acute colitis was induced by 2% dextran sodium sulfate (DSS), and colitis-associated CRC was induced by injecting azoxymethane (AOM), followed by three cycles of 2% DSS treatments. Colon tissues were collected from mice and analyzed by histology, immunohistochemistry and immunoblots. Organoids were generated from Setd2Vil-KO and control mice, and were stained with 7-AAD to detect apoptosis. We isolated intestinal epithelial cells (IECs), performed RNA-seq and H3K36me3 ChIP-seq analysis to uncover the mechanism. Results were validated in functional rescue experiments by N-acetyl-l-cysteine (NAC) treatment and transgenes expression in IECs. SETD2 expression was decreased in IBD patients and DSS-treated colitis mice. Setd2Vil-KO mice had abnormal loss of mucosa-producing goblet cells and antimicrobial peptide (AMP)-producing Paneth cells, and promoted early intestinal inflammation development. Consistent with the reduced SETD2 expression in IBD patients, Setd2Vil-KO mice exhibited increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption. Intestinal permeability was markedly increased in Setd2Vil-KO mice. Setd2 ablation drived inflammation-associated CRC. Deletion of Setd2 resulted in excess reactive oxygen species (ROS), which led to cellular apoptosis and the defects in barrier integrity. N-acetyl-l-cysteine (NAC) treatment in Setd2Vil-KO mice rescued epithelial barrier injury and apoptosis. Moreover, overexpression of antioxidase PRDX6 in Setd2Vil-KO IECs largely alleviated the overproductions of ROS and improved the cellular survival. Deficiency of Setd2 specifically in the intestine aggravates epithelial barrier disruption and inflammatory response in colitis via a mechanism dependent on oxidative stress. More importantly, we show that Setd2 depletion results in excess ROS by directly down-regulating PRDX6, an antioxidant protein that inhibit excess ROS. Thus, our results highlight an epigenetic mechanism by which Setd2 mediates oxidative stress to modulate intestinal epithelial homeostasis.
2020-09-25 | GSE151965 | GEO
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2023-03-01 | GSE222836 | GEO
Project description:Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFα production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFα production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production in preventing chronic dysregulated inflammation. Ly6Chi monocytes were sorted from lamina propria of WT or Nlrp6-/- mice at day 10 of AOM/2%DSS. RNA was extracted and hybridized to the mouse 2.1 ST array.
2016-03-27 | E-GEOD-79631 | biostudies-arrayexpress
Project description:In the present study we investigate the role of IL-4 receptor a subunit in intestinal inflammation using DSS-induced colitis model. Our finding suggest that IL-4Ra deficiency enhances intestinal mucosal barrier function through the upregulation of NOX1-dependent ROS production, thereby suppressing the development of intestinal inflammation.
2020-09-10 | GSE157754 | GEO
Project description:Background and Objectives: Antibiotic (ABx) therapy is associated with an increased risk for Crohn´s Disease but the underlying mechanisms are unknown. We observed high fecal serine protease activity (PA) to be a frequent side effect of ABx therapy in patients. The aim of the present study was to unravel whether this rise in PA may promote colitis development via detrimental effects on the large intestinal barrier. Design: Transwell experiments were used to assess the impact of high PA in ABx-treated patients or vancomycin/metronidazole (V/M)-treated mice on the epithelial barrier. Serine protease profiling was performed using LC-MS/MS analysis. The impact of high PA on the intestinal barrier in WT/IL10-/- mice and on colitis development in IL10-/- mice was investigated using V/M+/-oral serine protease inhibitor (AEBSF) treatment. Results: The ABx-induced high PA was found to be due to significantly increased levels of pancreatic proteases and to impair the epithelial barrier. In WT mice, the rise in PA caused a transient increase in intestinal permeability but did not affect susceptibility towards DSS-induced acute colitis. In IL10-/- mice, the rise in PA caused a lasting impairment of the intestinal barrier, which was associated with inflammatory activation of the large intestinal tissue. In the long term, the lasting increase in PA upon repeated V/M treatment aggravated colitis development in IL10-/-mice. Conclusion: High PA is a frequent adverse effect of ABx therapy which is detrimental to the large intestinal barrier and may contribute to the development of chronic inflammation in genetically susceptible individuals.
2018-05-11 | PXD007914 | Pride