在缺乏caspase-8和TNFR1的小鼠中,ZBP1和TRIF引发致命的亡
Margaret Solon1, Nianfeng Ge1, Shannon Hambro1
1Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.
Cell death and differentiation
|March 29, 2024
概括
细胞死亡途径,包括RIPK1,RIPK3和MLKL,在小鼠组织中具有特征. Z型核酸传感器ZBP1在胚胎死亡和围产期死亡中发挥着关键作用,揭示了对细胞死亡调节的新见解.
科学领域:
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
- 发展生物学 发展生物学
背景情况:
- 死细胞亡是一种受调节的临床细胞死亡形式.
- 它由RIPK3和MLKL激酶进行介导,特别是当caspase-8被抑制时.
- 关键的上游激活器包括死亡受体,TLR3,TLR4和ZBP1.
研究的目的:
- 在小鼠中创建RIPK1,RIPK3,MLKL和ZBP1表达的全面组织地图.
- 调查ZBP1和其他因素在胚胎死亡率和围产期死亡率中的作用.
- 为了阐明导致出生后亡的途径,如果没有caspase-8和TNFR1.
主要方法:
- 使用免疫组织化学 (IHC) 和现场杂交 (ISH) 试验.
- 在各种小鼠组织中分析了RIPK1,RIPK3,MLKL和ZBP1的表达模式.
- 基因淘汰赛小鼠模型 (Casp8-/-, Tnfr1-/-, Zbp1-/-, Trif-/-) 用于研究致死性和亡途径.
主要成果:
- RIPK1,RIPK3和MLKL在免疫细胞,内皮细胞和上皮细胞中表现出共同表达.
- ZBP1表达在免疫细胞中普遍存在,但在表皮细胞中更为可变.
- 在Casp8-/- Tnfr1-/-胚胎中ZBP1的升高先于致死,而ZBP1缺乏改善了生存率.
- 在Casp8-/- Tnfr1-/- Zbp1-/- 幼中,TRIF介导的亡有助于围产死亡.
- 在Casp8-/- Tnfr1-/- Trif-/- Zbp1-/-小鼠的产后死亡率表明RIPK1-依赖性亡通过替代死亡受体.
结论:
- 在小鼠组织中建立了关键亡媒介的详细表达图.
- 在没有caspase-8和TNFR1.1.的情况下,ZBP1对胚胎致死性至关重要.
- TRIF-依赖性亡有助于围产死亡率.
- 产后死亡率很可能是由RIPK1-依赖性亡引起的,其媒介是TNFR1.1.以外的死亡受体.
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