Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis

摘要

Mixed lineage kinase domain-like protein (Mlkl) was recently found to interact with receptor interacting protein 3 (Rip3) and to be essential for tumor necrosis factor (TNF)-induced programmed necrosis (necroptosis) in cultured cell lines.We have generated Mlkl-deficient mice by transcription activator-like effector nucleases (TALENs)-mediated gene disruption and found Mlkl to be dispensable for normal mouse development as well as immune cell development.Mlkl-deficient mouse embryonic fibroblasts (MEFs) and macrophages both showed resistance to necrotic but not apoptotic stimuli.Mlkl-deficient MEFs and macrophages were indistinguishable from wild-type cells in their ability to activate NF-κB,ERK,JNK,and p38 in response to TNF and lipopolysaccharides (LPS),respectively.Consistently,Mlkl-deficient macrophages and mice exhibited normal interleukin-1β (IL-1β),IL-6,and TNF production after LPS treatment.Mlkl deficiency protects mice from cerulean-induced acute pancreatitis,a necrosis-related disease,but has no effect on polymicrobiai septic shock-induced animal death.Our results provide genetic evidence for the role of Mlkl in necroptosis.