RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis

摘要: 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-κB-mediated cell survival inflammation well caspase-8 (CASP8)-dependent apoptotic or RIPK3/MLKL-dependent necroptotic death. The physiological relevance of this dual remained elusive because perinatal full knockout mice. To circumvent problem, we generated conditional mice, show that mice lacking intestinal epithelial cells (IECs) spontaneously develop severe associated with IEC apoptosis leading early This lethality was rescued antibiotic treatment, MYD88 deficiency tumour-necrosis factor (TNF) receptor deficiency, demonstrating importance commensal bacteria TNF Ripk1 phenotype. CASP8 but not RIPK3 inflammatory phenotype completely, indicating indispensable suppressing CASP8-dependent RIPK3-dependent necroptosis intestine. kinase-dead knock-in did exhibit any sign inflammation, suggesting RIPK1-mediated protection resides its kinase-independent platform function. Depletion organoid cultures sensitized them TNF-induced apoptosis, confirming vivo observations. Unexpectedly, TNF-mediated NF-κB activation intact these organoids. Our results demonstrate for IECs, ensuring homeostasis protecting epithelium from CASP8-mediated independently activity activation.