Universität zu Köln

Welz, Patrick-Simon ORCID: 0000-0001-8370-625X, Wullaert, Andy ORCID: 0000-0001-5012-654X, Vlantis, Katerina, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Fernandez-Majada, Vanesa, Ermolaeva, Maria, Kirsch, Petra, Sterner-Kock, Anja, van Loo, Geert and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2011). FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature, 477 (7364). S. 330 - 336. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Intestinal immune homeostasis depends on a tightly regulated cross talk between commensal bacteria, mucosal immune cells and intestinal epithelial cells (IECs)(1-4). 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(7-9), 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 NEMOIEC-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Welz, Patrick-Simon UNSPECIFIED orcid.org/0000-0001-8370-625X UNSPECIFIED Wullaert, Andy UNSPECIFIED orcid.org/0000-0001-5012-654X UNSPECIFIED Vlantis, Katerina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Fernandez-Majada, Vanesa UNSPECIFIED UNSPECIFIED UNSPECIFIED Ermolaeva, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirsch, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Sterner-Kock, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-489003
DOI:	10.1038/nature10273
Journal or Publication Title:	Nature
Volume:	477
Number:	7364
Page Range:	S. 330 - 336
Date:	2011
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEMO/IKK-GAMMA; DEFICIENT MICE; TNF-ALPHA; B-CELL; DEATH; REGULATOR; APOPTOSIS; DELETION; IMMUNITY; RIP3 Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48900