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Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury.

ABSTRACT: Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury.

PROVIDER: PRJNA1036441 | ENA |

REPOSITORIES: ENA

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Type III interferons induce pyroptosis in gut epithelial cells and delay tissue restitution upon acute intestinal injury.

Project description:To determine the transcriptional programs initiated by IFN-λ to delay tissue restitution, we isolated intestinal crypts from the small intestine of VilCREIfnlr1fl/fl mice or WT littermates that have been irradiated and performed targeted transcriptomics analysis

2024-04-01 | GSE247149 | GEO

Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

Project description:Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight on how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to Caspase-8 activation, and cleavage of Gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/Caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has important implications for IBD patients or individuals exposed to radiation therapies.

2024-11-01 | GSE277150 | GEO

Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

Project description:Tissue damage and repair are hallmarks of the inflammatory process. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight on how inflammatory mediators affect repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa driven by inflammation or genotoxicity. We found that type III, but not type I or II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed during the damage and repair process are then sensed by ZBP-1, leading to Caspase-8 activation, and cleavage of Gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays the re-epithelialization of the large or small intestine after colitis or irradiation, respectively. We also found that the type III interferon/ZBP1/Caspase-8/GSDMC pathway is activated in patients with inflammatory bowel disease (IBD). Our findings highlight a molecular signaling cascade initiated by type III interferons that delays intestinal tissue repair, which has important implications for IBD patients or individuals exposed to radiation therapies.

2024-11-01 | GSE276837 | GEO

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

Project description:Gasdermins are a family of structurally-related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic, mucosal inflammatory disorders is well-established, little is known of its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids, but instead, point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based actomyosin stress fibers dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects disrupting epithelial restitution/repair, which altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.

2022-01-30 | GSE191015 | GEO

Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

Project description:Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

| PRJNA1159204 | ENA

Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

Project description:Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

| PRJNA1160875 | ENA

GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

Project description:GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis

| PRJNA789330 | ENA

Eutherian interferons

Project description:Eutherian interferons

| PRJEB36709 | ENA

Neutrophil extracellular traps induce glomerular endothelial cell dysfunction and pyroptosis in diabetic kidney disease

Project description:Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After degrading NETs with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cell (GEC) injury. We also observed alleviated glomerulopathy and GEC injury in peptidylarginine deiminase 4 (PAD4)-knockout mice with streptozotocin-induced diabetes. In vitro, NET-induced GEC pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and high expression of pyroptosis-related proteins. Strengthening the GEC surface charge by oleylamine significantly inhibited NET-induced GEC pyroptosis. These results indicate that NET-induced alterations in GEC charge are associated with GEC pyroptosis in the pathogenesis of DKD and suggest that NETs are a potential therapeutic target for DKD.

2022-09-01 | GSE189875 | GEO

Elevated methionine flux drives pyroptosis evasion in persister cancer cells

Project description:Induction of cell death represents a primary goal of most anti-cancer treatments. Despite the efficacy of such approaches, a small population of “persisters” develop evasion strategies to therapy-induced cell death. While previous studies have identified mechanisms of resistance to apoptosis, the mechanisms by which persisters dampen other forms of cell death, such as pyroptosis, remain to be elucidated. Pyroptosis is a form of inflammatory cell death that involves formation of membrane pores, ion gradient imbalance, water inflow and membrane rupture. Herein, we investigate mechanisms by which cancer persisters resist pyroptosis, survive, then proliferate in the presence of tyrosine kinase inhibitors (TKI). Lung, prostate and esophageal cancer persister cells remaining after treatments exhibited several hallmarks indicative of pyroptosis resistance. The inflammatory attributes of persisters included chronic activation of inflammasome, STING, and type I interferons. Comprehensive metabolomic characterization uncovered that TKI-induced pyroptotic persisters display high methionine consumption and excessive taurine production. Elevated methionine flux or exogenous taurine maintained plasma membrane integrity via osmolyte-mediated effects. Increased dependency on methionine flux decreased the level of one carbon metabolism intermediate S-(5'-adenosyl)-L-homocysteine, a determinant of cell methylation capacity. The consequent increase in methylation potential induced DNA hypermethylation of genes regulating metal ion balance and intrinsic immune response. This enabled thwarting TKI resistance by using the hypomethylating agent decitabine. In summary, the evolution of resistance to pyroptosis can occur via a stepwise process of physical acclimation and epigenetic changes without existing or recurrent mutations.

2022-12-02 | GSE219044 | GEO

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