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

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.