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A Novel Role for Necroptosis in the Pathogenesis of Necrotizing Enterocolitis.
- Source :
-
Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2020; Vol. 9 (3), pp. 403-423. Date of Electronic Publication: 2019 Nov 19. - Publication Year :
- 2020
-
Abstract
- Background & Aims: Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by Toll-like receptor 4 (TLR4)-dependent intestinal inflammation and enterocyte death. Given that necroptosis is a proinflammatory cell death process that is linked to bacterial signaling, we investigated its potential role in NEC, and the mechanisms involved.<br />Methods: Human and mouse NEC intestine were analyzed for necroptosis gene expression (ie, RIPK1, RIPK3, and MLKL), and protein activation (phosphorylated RIPK3). To evaluate a potential role for necroptosis in NEC, the effects of genetic (ie, Ripk3 knockout or Mlkl knockout) or pharmacologic (ie, Nec1s) inhibition of intestinal inflammation were assessed in a mouse NEC model, and a possible upstream role of TLR4 was assessed in Tlr4-deficient mice. The NEC-protective effects of human breast milk and its constituent milk oligosaccharides on necroptosis were assessed in a NEC-in-a-dish model, in which mouse intestinal organoids were cultured as either undifferentiated or differentiated epithelium in the presence of NEC bacteria and hypoxia.<br />Results: Necroptosis was activated in the intestines of human and mouse NEC in a TLR4-dependent manner, and was up-regulated specifically in differentiated epithelium of the immature ileum. Inhibition of necroptosis genetically and pharmacologically reduced intestinal-epithelial cell death and mucosal inflammation in experimental NEC, and ex vivo in the NEC-in-a-dish system. Strikingly, the addition of human breast milk, or the human milk oligosaccharide 2 fucosyllactose in the ex vivo system, reduced necroptosis and inflammation.<br />Conclusions: Necroptosis is activated in the intestinal epithelium upon TLR4 signaling and is required for NEC development, and explains in part the protective effects of breast milk.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Disease Models, Animal
Enterocolitis, Necrotizing drug therapy
Enterocolitis, Necrotizing genetics
Enterocolitis, Necrotizing immunology
Enterocytes drug effects
Enterocytes immunology
Female
Humans
Infant, Newborn
Intestinal Mucosa drug effects
Mice
Mice, Knockout
Necroptosis drug effects
Protein Kinases genetics
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Signal Transduction drug effects
Signal Transduction genetics
Signal Transduction immunology
Toll-Like Receptor 4 genetics
Toll-Like Receptor 4 metabolism
Trisaccharides pharmacology
Trisaccharides therapeutic use
Up-Regulation
Enterocolitis, Necrotizing pathology
Enterocytes pathology
Intestinal Mucosa pathology
Milk, Human chemistry
Necroptosis immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2352-345X
- Volume :
- 9
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cellular and molecular gastroenterology and hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 31756560
- Full Text :
- https://doi.org/10.1016/j.jcmgh.2019.11.002