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激活ZBP1触发了造血干细胞和原始细胞死亡,导致小鼠的骨髓衰竭

Justine E Roderick-Richardson¹, Sung-Eun Lim¹, Sakiko Suzuki²

¹Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.

Proceedings of the National Academy of Sciences of the United States of America

|January 16, 2024

概括

骨髓衰竭 (BMF) 涉及血液形成干细胞的损失. 这项研究表明,RIPK1缺乏会通过亡和亡引发细胞死亡,由Z-DNA结合蛋白1 (ZBP1) 和干扰素- (IFNγ) 介导,导致BMF.

科学领域:

血液学血液学血液学
免疫学免疫学免疫学
细胞生物学细胞生物学

背景情况:

人类骨髓衰竭 (BMF) 综合征的特征是血造干细胞和原生细胞 (HSPC) 损失,但潜在的细胞死亡机制尚不清楚.
在BMF期间观察到瘤缩因子-α (TNFα) 和干扰素-γ (IFNγ) 的水平增加,这是已知的致死因子诱导剂,这是一个涉及RIPK1,RIPK3和MLKL的编程细胞死亡途径.

研究的目的:

在RIPK1缺陷的背景下阐明HSPC死亡的机制.
调查死细胞灭绝,死细胞灭绝,Z-DNA结合蛋白1 (ZBP1) 和特定细胞因子在调解BMF中的作用.

主要方法:

用RIPK1,RIPK3和MLKL缺陷的小鼠模型来研究BMF.
评估了ZBP1,IFNγ和TNFα受体信号对HSPC存活率和BMF进展的影响.

主要成果:

MLKL 缺乏,类似于 RIPK3 缺乏,在 RIPK1 缺乏的小鼠中改善了存活率和血液形成,表明亡和亡对 BMF 的贡献.
在RIPK1缺乏的细胞中,Z-DNA结合蛋白1 (ZBP1) 的高调,其核酸感应功能对HSPC死亡和BMF至关重要.
消去IFNγ信号传递,但没有TNFα受体信号传递,显著延长了RIPK1缺乏的小鼠的存活时间,确定IFNγ是HSPC死亡的关键媒介.

结论:

通过抑制ZBP1激活和随后的HSPC死亡,RIPK1在维持造血平衡中发挥着至关重要的作用.
在这个模型中,受ZBP1和IFNγ影响的亡和亡途径都对BMF的发病有所贡献.
准ZBP1或IFNγ信号可能为BMF综合征提供治疗策略.

关键词:

在 ZBP1 中,ZBP1 是灭症 (apoptosis) 是一种死亡的过程.骨髓功能衰竭骨髓功能衰竭血液形成血液形成尸体的死亡和死亡.

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