Publication Date:
2014-09-05
Description:
Receptor interacting protein kinase 1 (RIPK1) has an essential role in the signalling triggered by death receptors and pattern recognition receptors. RIPK1 is believed to function as a node driving NF-kappaB-mediated cell survival and inflammation as well as caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic cell death. The physiological relevance of this dual function has remained elusive because of the perinatal death of RIPK1 full knockout mice. To circumvent this problem, we generated RIPK1 conditional knockout mice, and show that mice lacking RIPK1 in intestinal epithelial cells (IECs) spontaneously develop severe intestinal inflammation associated with IEC apoptosis leading to early death. This early lethality was rescued by antibiotic treatment, MYD88 deficiency or tumour-necrosis factor (TNF) receptor 1 deficiency, demonstrating the importance of commensal bacteria and TNF in the IEC Ripk1 knockout phenotype. CASP8 deficiency, but not RIPK3 deficiency, rescued the inflammatory phenotype completely, indicating the indispensable role of RIPK1 in suppressing CASP8-dependent apoptosis but not RIPK3-dependent necroptosis in the intestine. RIPK1 kinase-dead knock-in mice did not exhibit any sign of inflammation, suggesting that RIPK1-mediated protection resides in its kinase-independent platform function. Depletion of RIPK1 in intestinal organoid cultures sensitized them to TNF-induced apoptosis, confirming the in vivo observations. Unexpectedly, TNF-mediated NF-kappaB activation remained intact in these organoids. Our results demonstrate that RIPK1 is essential for survival of IECs, ensuring epithelial homeostasis by protecting the epithelium from CASP8-mediated IEC apoptosis independently of its kinase activity and NF-kappaB activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takahashi, Nozomi -- Vereecke, Lars -- Bertrand, Mathieu J M -- Duprez, Linde -- Berger, Scott B -- Divert, Tatyana -- Goncalves, Amanda -- Sze, Mozes -- Gilbert, Barbara -- Kourula, Stephanie -- Goossens, Vera -- Lefebvre, Sylvie -- Gunther, Claudia -- Becker, Christoph -- Bertin, John -- Gough, Peter J -- Declercq, Wim -- van Loo, Geert -- Vandenabeele, Peter -- England -- Nature. 2014 Sep 4;513(7516):95-9. doi: 10.1038/nature13706.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] VIB Inflammation Research Center, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. ; Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. ; 1] VIB Inflammation Research Center, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium [3] VIB Bio Imaging Core Gent, Technologiepark 927, B-9052 Ghent, Belgium. ; Department of Medicine 1, Friedrich-Alexander-University, D-91054 Erlangen, Germany. ; 1] VIB Inflammation Research Center, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium [3] Methusalem program, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25186904" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anti-Bacterial Agents/pharmacology
;
*Apoptosis/drug effects
;
Caspase 8/genetics/metabolism
;
Cell Survival/drug effects
;
Epithelial Cells/*cytology/drug effects/*metabolism/pathology
;
Epithelium/drug effects/*metabolism/pathology
;
Female
;
Gene Deletion
;
*Homeostasis/drug effects
;
Inflammation/metabolism/pathology
;
Intestines/*cytology/drug effects/*metabolism/pathology
;
Male
;
Mice
;
Mice, Knockout
;
Myeloid Differentiation Factor 88/deficiency
;
NF-kappa B/metabolism
;
Necrosis
;
Organoids/cytology/drug effects/enzymology/metabolism
;
Protein Kinases/metabolism
;
Receptor-Interacting Protein Serine-Threonine
;
Kinases/deficiency/genetics/*metabolism
;
Receptors, Tumor Necrosis Factor, Type I/deficiency
;
Survival Analysis
;
Tumor Necrosis Factors/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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