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Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis

Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum(...

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Autores principales: Günther, Claudia, Martini, Eva, Wittkopf, Nadine, Amann, Kerstin, Weigmann, Benno, Neumann, Helmut, Waldner, Maximilian, Hedrick, Stephen M., Tenzer, Stefan, Neurath, Markus F., Becker, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373730/
https://www.ncbi.nlm.nih.gov/pubmed/21921917
http://dx.doi.org/10.1038/nature10400
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author Günther, Claudia
Martini, Eva
Wittkopf, Nadine
Amann, Kerstin
Weigmann, Benno
Neumann, Helmut
Waldner, Maximilian
Hedrick, Stephen M.
Tenzer, Stefan
Neurath, Markus F.
Becker, Christoph
author_facet Günther, Claudia
Martini, Eva
Wittkopf, Nadine
Amann, Kerstin
Weigmann, Benno
Neumann, Helmut
Waldner, Maximilian
Hedrick, Stephen M.
Tenzer, Stefan
Neurath, Markus F.
Becker, Christoph
author_sort Günther, Claudia
collection PubMed
description Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum(1). Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium(2). Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans(3). However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.
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spelling pubmed-33737302012-06-12 Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis Günther, Claudia Martini, Eva Wittkopf, Nadine Amann, Kerstin Weigmann, Benno Neumann, Helmut Waldner, Maximilian Hedrick, Stephen M. Tenzer, Stefan Neurath, Markus F. Becker, Christoph Nature Article Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum(1). Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium(2). Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans(3). However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8(ΔIEC)) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8(ΔIEC) mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8(ΔIEC) mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death. 2011-09-14 /pmc/articles/PMC3373730/ /pubmed/21921917 http://dx.doi.org/10.1038/nature10400 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Günther, Claudia
Martini, Eva
Wittkopf, Nadine
Amann, Kerstin
Weigmann, Benno
Neumann, Helmut
Waldner, Maximilian
Hedrick, Stephen M.
Tenzer, Stefan
Neurath, Markus F.
Becker, Christoph
Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title_full Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title_fullStr Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title_full_unstemmed Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title_short Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis
title_sort caspase-8 regulates tnf-alpha induced epithelial necroptosis and terminal ileitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373730/
https://www.ncbi.nlm.nih.gov/pubmed/21921917
http://dx.doi.org/10.1038/nature10400
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