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

Publication date: 25 April 2017
Source:Cell Reports, Volume 19, Issue 4
Author(s): Qun Zhao, XianJun Yu, HaiWei Zhang, YongBo Liu, XiXi Zhang, XiaoXia Wu, Qun Xie, Ming Li, Hao Ying, Haibing Zhang
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.

Graphical abstract

Teaser

Zhao et al. find 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.


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