RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice

Qun Zhao; XianJun Yu; HaiWei Zhang; YongBo Liu; XiXi Zhang; XiaoXia Wu; Qun Xie; Ming Li; Hao Ying; Haibing Zhang

doi:10.1016/j.celrep.2017.04.011

RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice

Cell Rep. 2017 Apr 25;19(4):798-808. doi: 10.1016/j.celrep.2017.04.011.

Authors

Qun Zhao¹, XianJun Yu², HaiWei Zhang¹, YongBo Liu¹, XiXi Zhang¹, XiaoXia Wu¹, Qun Xie³, Ming Li¹, Hao Ying⁴, Haibing Zhang⁵

Affiliations

¹ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
² Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital & School of Basic Medical Sciences, Hubei University of Medicine, Shiyan 442000, China.
³ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
⁴ Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
⁵ Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: hbzhang@sibs.ac.cn.

PMID: 28445730
DOI: 10.1016/j.celrep.2017.04.011

Abstract

RIPK3 mediates cell death and regulates inflammatory responses. Although genetic studies have suggested that RIPK3-MLKL-mediated necroptosis leads to embryonic lethality in Fadd or Caspase-8-deficient mice, the exact mechanisms are not fully understood. Here, we generated Ripk3 mutant mice by altering the RIPK3 kinase domain (Ripk3^Δ/Δ mice), thus abolishing its kinase activity. Ripk3^Δ/Δ cells were resistant to necroptosis stimulation in vitro, and Ripk3^Δ/Δ mice were protected from necroptotic diseases. Although the Ripk3^Δ/Δ mutation rescued embryonic lethality in Fadd^-/- embryos, Fadd^-/-Ripk3^Δ/Δ mice died within 1 day after birth due to massive inflammation. These results indicate that Ripk3 ablation rescues embryonic lethality in Fadd-deficient mice by suppressing two RIPK3-mediating processes: necroptosis during embryogenesis and inflammation during postnatal development in Fadd^-/- mice.

Keywords: Fadd; RIPK3; cell death; embryogenesis; inflammation; kinase activity; necroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis* / drug effects
Caspase 8 / genetics
Caspase 8 / metabolism
Ceruletide / toxicity
Chemokines / metabolism
Cytokines / analysis
Cytokines / metabolism
Embryo, Mammalian / metabolism
Embryonic Development / drug effects
Fas-Associated Death Domain Protein / deficiency
Fas-Associated Death Domain Protein / genetics*
HEK293 Cells
Humans
Inflammation
Lipopolysaccharides / toxicity
Macrophages / cytology
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Knockout
Mutagenesis
Necrosis
Oligopeptides / pharmacology
Pancreatitis / chemically induced
Pancreatitis / pathology
Phosphorylation
Protein Kinases / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

Chemokines
Cytokines
Fadd protein, mouse
Fas-Associated Death Domain Protein
Lipopolysaccharides
Oligopeptides
benzyloxycarbonyl-valyl-alanyl-aspartic acid
Ceruletide
MLKL protein, mouse
Protein Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk3 protein, mouse
Caspase 8