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

By C. Günther, Eva Martini, Nadine Wittkopf, K. Amann, B. Weigmann, H. Neumann, M. Waldner, S. Hedrick, S. Tenzer, Markus F. Neurath and 1 more. Nature, 2011

798 citations recorded by the source corpus.

Dysfunction of the intestinal epithelium is believed to result in the 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. In healthy individuals, the intestinal epithelium maintains a physical barrier, established by the tight contact of cells. Moreover, 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. Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a possible pathogenic mechanism driving Crohn’s disease in humans. However, the regulation of epithelial cell death and its role in intestinal homeostasis remain poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IECs) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells, indicating dysregulated antimicrobial immune cell functions of the intestinal epithelium. Casp8ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumour necrosis factor (TNF)-α, was associated with increased expression of receptor-interacting protein 3 (Rip3; also known as Ripk3) and could be inhibited on blockade of necroptosis. Lastly, 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. Together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/92284a5ebaebf705b21fe1b3570325c1de451e9d

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In Immunology

1. T. Kanneganti
2. R. Malireddi
3. S. Kesavardhana

In Molecular Biology

1. T. Kanneganti
2. R. Malireddi
3. S. Kesavardhana
4. Yaqiu Wang

Citations in the corpus

• ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis) (2019, background): “Studies focused on the RHIM domain-containing proteins (RIPK1 and RIPK3) and their crosstalk with FADD–caspase-8–mediated pathways improved our understanding of the apoptotic and necroptotic pathways and their intricate regulatory mechanisms (Holler et al., 2000; He et al., 2009; Zhang et al., 2009;”
• Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome (2019, background): “Similarly, mice deficient in the caspase-8- gene, an intestinal epithelial cell-specific gene, experienced spontaneous ileitis [188].”