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Embryonic Lethality and Host Immunity of RelA-Deficient Mice Are Mediated by Both Apoptosis and Necroptosis
Chengxian Xu1, Xiaoxia Wu1, Xixi Zhang1
1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; and.
Abstract:
In mammalian cells, signaling pathways triggered by TNF can be switched from NF-κB activation to apoptosis and/or necroptosis. The in vivo mechanisms underlying the mutual regulation of these three signaling pathways are poorly understood. In this article, we report that the embryonic lethality of RelA-deficient mice is partially prevented by the deletion of Rip3 or Mlkl, but it is fully rescued by the combined ablation of Fadd and Rip3 or Mlkl or by blocking RIP1 kinase activity (RIP1K45A). RelA triple-knockout (TKO) and RelA mice displayed bacterial pneumonia leading to death ∼2 wk after birth. Moreover, RelA mice, but not TKO mice, developed severe inflammation associated with inflammatory skin lesion. Antibiotic treatment improved bacterial pneumonia, extended the lifespan of TKO and RelA mice, and alleviated skin inflammation in RelA mice. These results show the mechanisms underlying the in vivo mutual regulation between NF-κB activation and the cell death pathway and provide new insights into this interplay in embryonic development and host immune homeostasis.
Insights
Tumor necrosis factor (TNF) signaling in mammals can lead to NF-κB activation or cell death. This study reveals how blocking RIP1 kinase activity rescues embryonic lethality in RelA-deficient mice, clarifying NF-κB and cell death pathway interplay.
Area of Science:
- Immunology
- Cell Biology
- Developmental Biology
Background:
- Mammalian cells exhibit complex signaling pathways involving TNF, which can activate NF-κB or induce apoptosis/necroptosis.
- The precise in vivo mechanisms governing the interplay between NF-κB activation and cell death pathways remain incompletely understood.
Purpose of the Study:
- To elucidate the in vivo regulatory mechanisms between NF-κB activation and TNF-induced cell death pathways.
- To investigate the role of these pathways in embryonic development and host immune homeostasis.
Main Methods:
- Generating and analyzing genetically modified mice, including RelA-deficient, Rip3-deficient, Mlkl-deficient, Fadd-deficient, and combinations thereof.
- Utilizing a RIP1 kinase-dead mutant (RIP1K45A) to block RIP1 kinase activity.
- Administering antibiotics to assess their impact on survival and inflammation.
Main Results:
- Embryonic lethality in RelA-deficient mice was partially rescued by Rip3 or Mlkl deletion and fully rescued by combined Fadd and Rip3/Mlkl ablation or RIP1 kinase inhibition.
- RelA-deficient mice exhibited bacterial pneumonia and inflammation, with antibiotic treatment improving survival and alleviating symptoms.
- Triple-knockout mice lacking RelA showed distinct phenotypes compared to RelA-deficient mice, highlighting specific roles.
Conclusions:
- The study uncovers critical in vivo mechanisms regulating the balance between NF-κB activation and cell death.
- These findings offer new insights into the interplay of these pathways during embryonic development and in maintaining immune homeostasis.
- Targeting RIP1 kinase activity presents a potential strategy for modulating these signaling pathways.
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