An IRF1-dependent Pathway of TNFα-induced Shedding in Intestinal Epithelial Cells.
J Crohns Colitis
; 16(1): 133-142, 2022 Jan 28.
Article
em En
| MEDLINE
| ID: mdl-34309645
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Fator de Necrose Tumoral alfa
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Células Epiteliais
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Fator Regulador 1 de Interferon
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Mucosa Intestinal
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article