Journal Article

FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation

Pasparakis, Manolis, Wullaert, Andy, Vlantis, Katerina, Kondylis, Vangelis, Ermolaeva, Maria, van Loo, Geert, Welz, Patrick-Simon, Fernández-Majada, Vanesa, Kirsch, Petra, Sterner-Kock, Anja

2011

Overview

Epithelial cell death in intestinal inflammatory disease Two groups identify the regulation of death-receptor-induced necroptosis as an epithelial intrinsic mechanism that is important for the maintenance of immune homeostasis and the prevention of intestinal inflammation in mice. Welz et al . describe an unexpected physiological function for FADD (Fas-associated protein with death domain), an adaptor protein required for death-receptor-induced apoptosis. Mice with intestinal epithelial specific knockout of FADD develop severe colon inflammation due to increased death of FADD-deficient colonic epithelial cells. Günther et al . report a novel and unexpected function of caspase-8 in maintaining immune homeostasis in the gut. Caspase-8 expression by gut epithelial cells is shown to protect mice from TNF-mediated Paneth cell death and intestinal inflammation. Increased expression of the protein RIP3 was associated with the TNF-induced pathology, and elevated RIP3 expression was also found in intestinal Paneth cells of patients with Crohn's disease. Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs) 1 , 2 , 3 , 4 . Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood 1 , 5 . Here we show that mice with IEC-specific knockout of FADD (FADD IEC-KO ), an adaptor protein required for death-receptor-induced apoptosis 6 , spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis 7 , 8 , 9 , prevented the development of spontaneous pathology in both the small intestine and colon of FADD IEC-KO mice, demonstrating that intestinal inflammation is triggered by RIP3-dependent death of FADD-deficient IECs. Epithelial-specific inhibition of CYLD, a deubiquitinase that regulates cellular necrosis 10 , prevented colitis development in FADD IEC-KO but not in NEMO IEC-KO mice 11 , showing that different mechanisms mediated death of colonic epithelial cells in these two models. In FADD IEC-KO mice, TNF deficiency ameliorated colon inflammation, whereas MYD88 deficiency and also elimination of the microbiota prevented colon inflammation, indicating that bacteria-mediated Toll-like-receptor signalling drives colitis by inducing the expression of TNF and other cytokines. However, neither CYLD, TNF or MYD88 deficiency nor elimination of the microbiota could prevent Paneth cell loss and enteritis in FADD IEC-KO mice, showing that different mechanisms drive RIP3-dependent necrosis of FADD-deficient IECs in the small and large bowel. Therefore, by inhibiting RIP3-mediated IEC necrosis, FADD preserves epithelial barrier integrity and antibacterial defence, maintains homeostasis and prevents chronic intestinal inflammation. Collectively, these results show that mechanisms preventing RIP3-mediated epithelial cell death are critical for the maintenance of intestinal homeostasis and indicate that programmed necrosis of IECs might be implicated in the pathogenesis of inflammatory bowel disease, in which Paneth cell and barrier defects are thought to contribute to intestinal inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1933 / 692/420 / 692/699/249/2510/257 / Animals / Apoptosis / Biological and medical sciences / Chronic Disease / Colitis - enzymology / Colitis - metabolism / Colitis - pathology / Colleges & universities / Colon / Colon - enzymology / Colon - metabolism / Colon - pathology / Cysteine Endopeptidases - metabolism / Enteritis - enzymology / Enteritis - metabolism / Enteritis - pathology / Epithelial Cells - enzymology / Epithelial Cells - metabolism / Epithelial Cells - pathology / Fas-Associated Death Domain Protein - deficiency / Fas-Associated Death Domain Protein - metabolism / Gastroenterology. Liver. Pancreas. Abdomen / Homeostasis / Humanities and Social Sciences / Inflammatory bowel disease / Inflammatory Bowel Diseases - enzymology / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Intracellular Signaling Peptides and Proteins - deficiency / Intracellular Signaling Peptides and Proteins - metabolism / letter / Medical sciences / Metagenome - physiology / Mice / Mortality / multidisciplinary / Myeloid Differentiation Factor 88 - deficiency / Myeloid Differentiation Factor 88 - metabolism / Necrosis / Other diseases. Semiology / Paneth Cells - pathology / Pathogenesis / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Receptor-Interacting Protein Serine-Threonine Kinases - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Tumor Necrosis Factors - deficiency