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Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis.

ABSTRACT: Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5 ^ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5 ^fl/fl ) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5 ^ΔIEC mice compared to control Atg5 ^fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5 ^ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5 ^ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.

SUBMITTER: Nishino K

PROVIDER: S-EPMC8045999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice.

Project description:Intestinal epithelial cell (IEC) STAT3 is required for wound healing following acute dextran sodium sulfate (DSS) injury. We hypothesized that loss of IEC STAT3 would promote the development of chronic colitis following acute DSS injury.Colitis was induced in IEC-specific STAT3-deficient mice (STAT3)[INCREMENT]IEC and littermate controls (STAT3 Flx/Flx) with 4% DSS for 7 days, followed by water consumption for 21 days. Epithelial and immune mediators and severity of colitis were determined.Survival, colon length, and histologic injury were significantly worse at day 28 in STAT3[INCREMENT]IEC mice. IEC proliferation and apoptosis did not vary by genotype at day 14 or day 28. The colonic lamina propria frequency of pSTAT3* cells was increased at day 28 and correlated with histologic injury in STAT3 [INCREMENT]IEC mice. The frequency of colonic F480* pSTAT3* macrophages and CD3* pSTAT3* T lymphocytes were increased in STAT3[INCREMENT]IEC mice as compared with STAT3 Flx/Flx controls. In STAT3[INCREMENT]IEC mice, colonic expression of STAT3 target genes Reg3? and Reg3?, which mediate epithelial restitution, were significantly decreased, whereas expression of interleukin (IL)-17a, IFN?, CXCL2, CXCL10, and CCL2 were significantly increased and correlated with the increase in histologic severity at day 28(P < 0.05). IL-17a expression also correlated with the increased lamina propria frequency of CD3* pSTAT3* T lymphocytes.Loss of intestinal epithelial STAT3 leads to more severe chronic inflammation following acute injury, which is not accounted for by a sustained defect in epithelial proliferation or apoptosis 7 or 21 days after 1 cycle of DSS but rather defective REG3 expression and expansion of pSTAT3* lymphocytes and IL-17A expression.

| S-EPMC4330009 | biostudies-literature

Intestinal Epithelial Cell-Related Alternative Splicing Events in Dextran Sodium Sulfate-Induced Acute Colitis.

Project description:BackgroundAlternative splicing of pre-messenger RNA is recognized as the crucial mechanism for gene expression regulation and proteome diversity generation. Alternative splicing has been found to be related to the pathogenesis of inflammatory bowel disease. The aim of this study was to identify the alternative splicing events in intestinal epithelial cells from mouse models of acute colitis and expand the understanding of the pathogenesis of inflammatory bowel disease.MethodsThe acute colitis mouse models were constructed, and intestinal epithelial cells of the colon were isolated for RNA sequence. The replicate Multivariate Analysis of Transcript Splicing software was used to analyze the alternative splicing events. The functional analysis was performed on genes with significant differential alternative splicing events. The alternative splicing events of picked genes were validated by reverse transcription polymerase chain reaction.ResultsA total of 340 significant differential alternative splicing events (from 293 genes) were screened out in acute colitis, and the alternative splicing events of CDK5-regulatory subunit associated protein 3 and TRM5 tRNA methyltransferase 5 were validated. The functional analysis showed that differential alternative splicing events in acute colitis participate in the apoptotic process, and the alternative splicing events of 3 genes (BCL2/adenovirus E1B-interacting protein 2, tumor necrosis factor receptor-associated factor 1, and tumor necrosis factor receptor-associated factor 7) were validated by reverse transcription polymerase chain reaction.ConclusionThis study pointed out the potential impact of different alternative splicing in acute colitis.

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Colonic Epithelial Circadian Disruption Worsens Dextran Sulfate Sodium-Induced Colitis.

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Transgenic overexpression of ITGB6 in intestinal epithelial cells exacerbates dextran sulfate sodium-induced colitis in mice.

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| S-EPMC7933932 | biostudies-literature

Inhibition of HtrA2 alleviated dextran sulfate sodium (DSS)-induced colitis by preventing necroptosis of intestinal epithelial cells.

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Bifidobacterium longum alleviates dextran sulfate sodium-induced colitis by suppressing IL-17A response: involvement of intestinal epithelial costimulatory molecules.

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Close Homolog of L1 Deficiency Exacerbated Intestinal Epithelial Barrier Function in Mouse Model of Dextran Sulfate Sodium-Induced Colitis.

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Heme ameliorates dextran sodium sulfate-induced colitis through providing intestinal macrophages with noninflammatory profiles.

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| S-EPMC6099887 | biostudies-literature

<i>Clostridium butyricum</i> alleviates dextran sulfate sodium-induced experimental colitis and promotes intestinal lymphatic vessel regeneration in mice.

Project description:BackgroundInflammatory bowel disease (IBD) is the most common precancerous lesion of colitis-associated colon cancer (CAC). Studies have confirmed that pathological changes in intestinal lymphatic vessels (LVs) significantly promoted the development of IBD-associated carcinogenesis. An imbalance in the microecology of the intestinal flora is a key factor in the progression of IBD. As a result, therapeutic techniques that focus on the relationship between LV regeneration and flora management might be a potential treatment strategy.MethodsWe investigated the role of Clostridium butyricum (C butyricum) in a dextran sulfate sodium (DSS)-induced IBD mouse model. Balb/c mice were given 3% DSS in their drinking water for 8 days to produce acute colitis and simultaneously administrated with C butyricum for 12 days. Hematoxylin and eosin (H&E) staining was used to evaluate the degree of colitis tissue damage. Levels of the lymphatic endothelial cell (LEC)-specific marker LYVE-1 and intestinal expressions of pro-lymphatic vascular endothelial growth factor (VEGF)-C and VEGF-D were determined using immunohistochemical assays.ResultsIn a DSS-induced IBD mouse model, we found that butyric acid-producing C butyricum significantly reduced disease activity index (DAI) scores in mice, reversed the shortening of the colon, weakened the degree of damage to colonic epithelial tissues, inhibited lymphocyte infiltration, and reduced pathological damage to the colon. To our knowledge, this is the first time that tissue expressions of LYVE-1, VEGF-C, and VEGF-D have been seen to increase in IBD-model mice after treatment with C butyricum.ConclusionsOur findings suggest that C butyricum might alleviate IBD in DSS-induced IBD-model mice by promoting intestinal LV regeneration.

| S-EPMC9011313 | biostudies-literature