title: FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation.
abstract: Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs). Epithelial barrier disruption is considered to be a potential cause of inflammatory bowel disease; however, the mechanisms regulating intestinal epithelial integrity are poorly understood. Here we show that mice with IEC-specific knockout of FADD (FADD(IEC-KO)), an adaptor protein required for death-receptor-induced apoptosis, spontaneously developed epithelial cell necrosis, loss of Paneth cells, enteritis and severe erosive colitis. Genetic deficiency in RIP3, a critical regulator of programmed necrosis, 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, prevented colitis development in FADD(IEC-KO) but not in NEMO(IEC-KO) mice, 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.
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
authors.forename: Patrick-Simon
authors.initials: PS
authors.lastname: Welz
authors.forename: Andy
authors.initials: A
authors.lastname: Wullaert
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlantis
authors.forename: Vangelis
authors.initials: V
authors.lastname: Kondylis
authors.forename: Vanesa
authors.initials: V
authors.lastname: Fernández-Majada
authors.forename: Maria
authors.initials: M
authors.lastname: Ermolaeva
authors.forename: Petra
authors.initials: P
authors.lastname: Kirsch
authors.forename: Anja
authors.initials: A
authors.lastname: Sterner-Kock
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D003092:Colitis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D004751:Enteritis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism; D054892:Metagenome / Q000502:physiology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D009336:Necrosis; D019879:Paneth Cells / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000172:deficiency
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C514981:NEMO protein, mouse; D048069:Tumor Necrosis Factors; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases