title: RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis.
abstract: Necroptosis has emerged as an important pathway of programmed cell death in embryonic development, tissue homeostasis, immunity and inflammation. RIPK1 is implicated in inflammatory and cell death signalling and its kinase activity is believed to drive RIPK3-mediated necroptosis. 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.
authors.affiliation: 1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
authors.forename: Marius
authors.initials: M
authors.lastname: Dannappel
authors.affiliation: 1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlantis
authors.affiliation: 1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
authors.forename: Snehlata
authors.initials: S
authors.lastname: Kumari
authors.affiliation: 1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
authors.forename: Apostolos
authors.initials: A
authors.lastname: Polykratis
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Chun
authors.initials: C
authors.lastname: Kim
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Laurens
authors.initials: L
authors.lastname: Wachsmuth
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Eftychi
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Corona
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hermance
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Zelic
authors.affiliation: Tierforschungszentrum, University of Ulm, Albert-Einstein-Allee 11, D-89081 Ulm, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kirsch
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Marijana
authors.initials: M
authors.lastname: Basic
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Bleich
authors.affiliation: 1] Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2].
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelliher
authors.affiliation: 1] Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany [2].
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000473:pathology; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009336:Necrosis; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000473:pathology
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8