RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice
Open accessAbstract
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.
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Embryonic lethality imposed on mice by loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults.
“Thus, the embryonic lethality imposed on mice by the loss of Casp8 or Fadd can be rescued by concurrent ablation of Ripk3 or Mlkl, even though these double knockout animals generally display lymphoproliferative and/or systemic autoimmune disorders as adults [432, 466, 484, 485].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [484]
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References 64 · Cited by 49
- Authors
- Zhao, Q., Yu, X., Zhang, H., Liu, Y., Zhang, X., Wu, X., Xie, Q., Li, M., Ying, H., & Zhang, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Hubei University of Medicine (CN)
- Second Military Medical University (CN)
- Corresponding author
- Zhang, Haibing
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 19
- Issue
- 4
- Pages
- 798-808
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2609226509
- Cited by
- 49
- References
- 64
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 4
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Thomas Jefferson University
- National Natural Science Foundation of China (31571426, 81502548)
- Ministry of Science and Technology of the People's Republic of China (2016YFA0500100, 2016YFC1304900)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- RIPK3, necroptosis, FADD, embryonic lethality, MLKL, caspase-8, programmed cell death
- MeSH terms
- Animals, Ceruletide, Embryo, Mammalian, Humans, Inflammation, Lipopolysaccharides, Macrophages, Necrosis, Oligopeptides, Pancreatitis, Phosphorylation, Protein Kinases, Cytokines, Mutagenesis, Apoptosis, Mice, Knockout, Chemokines, Embryonic Development, Mice, Caspase 8, Fas-Associated Death Domain Protein, Receptor-Interacting Protein Serine-Threonine Kinases, HEK293 Cells
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