Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis
Intestinal epithelial Caspase-8 signaling is essential to prevent necroptosis during Salmonella Typhimurium induced enteritis
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DOI：
10.1038/s41385-018-0011-x
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发表时间：
2018-07-01
影响因子：
8
通讯作者：
Guenther, Claudia
中科院分区：
文献类型：
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作者：
Hefele, Manuela;Stolzer, Iris;Guenther, Claudia
虽然诱导宿主细胞死亡是细菌性胃肠炎的关键步骤，但其分子调控仍未完全确定。为了扩大我们的知识，我们研究了中央细胞死亡调节因子Caspase-8在鼠伤寒沙门氏菌反应中的作用。在这里，我们发现肠道沙门氏菌病与肠道上皮细胞(IECS)宿主细胞死亡机制成员的强烈上调有关，这表明消除受感染的IECS是一种宿主防御策略。事实上，Casp8(Delta IEC)小鼠在感染后表现出严重的组织损伤和高致死率。RIPK3或MLKL的额外缺失挽救了Casp8(Delta IEC)小鼠的上皮细胞死亡和致死性，证明了Caspase-8作为坏死性下垂的负调控因子的关键作用。虽然Casp8(Delta IEC)Tnfr1(-/-)小鼠感染后存活率提高，但组织破坏与Casp8(Delta IEC)小鼠相似，表明坏死性下垂部分依赖于TNF-α信号。虽然在感染的早期阶段，抗菌肽的分泌没有受到损害，但似乎需要功能性的Caspase-8来控制病原体的定植。综上所述，这些结果表明，Caspase-8在预防鼠伤寒沙门氏菌诱导的肠炎和通过两种不同的机制确保宿主生存方面是必不可少的：维持肠道屏障功能和限制病原体定植。
Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8(Delta IEC) mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8(Delta IEC) mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8(Delta IEC)Tnfr1(-/-) mice showed improved survival after infection, tissue destruction was similar to Casp8(Delta IEC) mice, indicating that necroptosis partially depends on TNF-alpha signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.