[PDF][PDF] RIPK3 mediates necroptosis during embryonic development and postnatal inflammation in Fadd-deficient mice

Q Zhao, XJ Yu, HW Zhang, YB Liu, XX Zhang, XX Wu… - Cell reports, 2017 - cell.com
Q Zhao, XJ Yu, HW Zhang, YB Liu, XX Zhang, XX Wu, Q Xie, M Li, H Ying, H Zhang
Cell reports, 2017cell.com
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 …
Summary
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 (Ripk3Δ/Δ mice), thus abolishing its kinase activity. Ripk3Δ/Δ cells were resistant to necroptosis stimulation in vitro, and Ripk3Δ/Δ mice were protected from necroptotic diseases. Although the Ripk3Δ/Δ mutation rescued embryonic lethality in Fadd−/− embryos, Fadd−/− Ripk3Δ/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.
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