An IRF1-dependent Pathway of TNFα-induced Shedding in Intestinal Epithelial Cells. (26th July 2021)

• Record Type: Journal Article
• Authors: Tan, Gao; Huang, Chongyang; Chen, Jiaye; Chen, Bingxia; Shi, Yanqiang; Zhi, Fachao
• Is Part Of: Journal of Crohn's and colitis. Volume 16:Number 1(2022)
• Page Start: 133
• Page End: 142
• Publication Date: 2021-07-26
• Subjects: Inflammatory bowel disease -- intestinal epithelial cell -- epithelial shedding -- pyroptosis -- interferon regulatory factor 1; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjab134
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background: Shedding of intestinal epithelial cells [IECs] is a potent cause of barrier loss which plays an important role in the pathogenesis of inflammatory bowel disease [IBD]. TNFα can induce IEC shedding, but little is known about this process. Methods: To investigate the molecular mechanism regulating IEC shedding, mice lacking interferon regulatory factor1 [IRF1], caspase-3, or gasdermin E [GSDME] and their control wild-type [WT] littermates were intravenously injected with tumour necrosis factor alpha [TNFα] to establish an IEC shedding model. A dual-luciferase reporter assay and a chromatin immunoprecipitation assay were used to determine the role of IRF1 in regulating caspase-3 expression. Results: TNFα administration induced obvious IEC shedding in WT mice, but IRF1 -/- and caspase-3 -/- mice were completely protected from TNFα-induced IEC shedding. As a critical transcription factor, IRF1 was found to be required for caspase-3 expression in IECs by binding to IRF1-binding sites in the caspase-3 promoter. In WT mice, plasma membrane integrity was disrupted in shed IECs; these cells were swollen and contained GSDME-N terminal [NT] fragments which are responsible for the induction of pyroptosis. However, in GSDME -/- mice, plasma membrane integrity was not disrupted in shed IECs, which were not swollen and did not contain GSDME-NT, indicating that GSDME converted TNFα-induced IEC shedding into a pyroptotic cell death process. In addition, IRF1 deficiency resulted in decreases in mucosal inflammation and mucosal bacteria levels in TNFα-challenged colons. Conclusions: IRF1 deficiency maintains intestinal barrier integrity by restricting TNFα-induced IEC shedding.