Xu Chengxian, Wu Xiaoxia, Zhang Xixi, Xie Qun, Fan Cunxian, Zhang Haibing
Key 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.
Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
J Immunol. 2018 Jan 1;200(1):271-285. doi: 10.4049/jimmunol.1700859. Epub 2017 Nov 22.
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 -deficient mice is partially prevented by the deletion of or but it is fully rescued by the combined ablation of and or or by blocking RIP1 kinase activity (RIP1). triple-knockout (TKO) and mice displayed bacterial pneumonia leading to death ∼2 wk after birth. Moreover, mice, but not TKO mice, developed severe inflammation associated with inflammatory skin lesion. Antibiotic treatment improved bacterial pneumonia, extended the lifespan of TKO and mice, and alleviated skin inflammation in 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.
在哺乳动物细胞中，由肿瘤坏死因子（TNF）触发的信号通路可从核因子κB（NF-κB）激活转换为凋亡和/或坏死性凋亡。这三种信号通路相互调节的体内机制尚不清楚。在本文中，我们报告称，缺失 或 可部分预防 -缺陷小鼠的胚胎致死性，但通过联合缺失 和 或 或通过阻断受体相互作用蛋白1激酶（RIP1）的活性可完全挽救其胚胎致死性。三联敲除（TKO）小鼠和 小鼠在出生后约2周出现细菌性肺炎并导致死亡。此外， 小鼠而非TKO小鼠出现与炎性皮肤病变相关的严重炎症。抗生素治疗改善了细菌性肺炎，延长了TKO小鼠和 小鼠的寿命，并减轻了 小鼠的皮肤炎症。这些结果揭示了NF-κB激活与细胞死亡通路之间体内相互调节的机制，并为胚胎发育和宿主免疫稳态中的这种相互作用提供了新的见解。
