Universität zu Köln

Dannappel, Marius, Vlantis, Katerina, Kumari, Snehlata, Polykratis, Apostolos ORCID: 0000-0001-6720-3302, Kim, Chun ORCID: 0000-0001-9497-708X, Wachsmuth, Laurens, Eftychi, Christina, Lin, Juan, Corona, Teresa, Hermance, Nicole, Zelic, Matija, Kirsch, Petra, Basic, Marijana, Bleich, Andre, Kelliher, Michelle and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2014). RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature, 513 (7516). S. 90 - 107. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation(1-8). RIPK1 is implicated in inflammatory and cell death signalling(9-13) and its kinase activity is believed to drive RIPK3-mediated necroptosis(14,15). Here we show that kinase-independent scaffolding RIPK1 functions regulate homeostasis and prevent inflammation in barrier tissues by inhibiting epithelial cell apoptosis and necroptosis. Intestinal epithelial cell (IEC)-specific RIPK1 knockout caused IEC apoptosis, villus atrophy, loss of goblet and Paneth cells and premature death in mice. This pathology developed independently of the microbiota and of MyD88 signalling but was partly rescued by TNFR1 (also known as TNFRSF1A) deficiency. Epithelial FADD ablation inhibited IEC apoptosis and prevented the premature death of mice with IEC-specific RIPK1 knockout. However, mice lacking both RIPK1 and FADD in IECs displayed RIPK3-dependent IEC necroptosis, Paneth cell loss and focal erosive inflammatory lesions in the colon. Moreover, a RIPK1 kinase inactive knock-in delayed but did not prevent inflammation caused by FADD deficiency in IECs or keratinocytes, showing that RIPK3-dependent necroptosis of FADD-deficient epithelial cells only partly requires RIPK1 kinase activity. Epidermis-specific RIPK1 knockout triggered keratinocyte apoptosis and necroptosis and caused severe skin inflammation that was prevented by RIPK3 but not FADD deficiency. These findings revealed that RIPK1 inhibits RIPK3-mediated necroptosis in keratinocytes in vivo and identified necroptosis as a more potent trigger of inflammation compared with apoptosis. Therefore, RIPK1 is a master regulator of epithelial cell survival, homeostasis and inflammation in the intestine and the skin.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dannappel, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Vlantis, Katerina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumari, Snehlata UNSPECIFIED UNSPECIFIED UNSPECIFIED Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED Kim, Chun UNSPECIFIED orcid.org/0000-0001-9497-708X UNSPECIFIED Wachsmuth, Laurens UNSPECIFIED UNSPECIFIED UNSPECIFIED Eftychi, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Lin, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED Corona, Teresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermance, Nicole UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelic, Matija UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirsch, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Basic, Marijana UNSPECIFIED UNSPECIFIED UNSPECIFIED Bleich, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelliher, Michelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-428972
DOI:	10.1038/nature13608
Journal or Publication Title:	Nature
Volume:	513
Number:	7516
Page Range:	S. 90 - 107
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NECROSIS-FACTOR RECEPTOR; KAPPA-B ACTIVATION; IN-VIVO; CELL; MICE; KINASE; DELETION; KERATINOCYTES; INFLAMMATION; DEFICIENT Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/42897