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S100A8 / A9 中性粒细胞诱导线粒体功能障碍和PANoptosis通过线粒体复合物I缺乏症在败血症期间内皮细胞

Yanghanzhao Wang^1,2,3, Yuxin Shi^1,2,3, Yuwen Shao^1,2,3

¹Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Cell death & disease

|June 28, 2024

概括

高水平的S100a8/a9蛋白质通过损害线粒体功能和激活PANoptosis,导致败血症诱导的内皮功能障碍. S100A8是导致败血症预后不佳的危险因素.

科学领域:

细胞生物学细胞生物学
免疫学免疫学免疫学
线粒体生物学线粒体生物学

背景情况:

由中性粒细胞释放的S100a8/a9蛋白与炎症性疾病有关.
之前的研究表明S100a8/a9可以诱导内皮细胞亡.
在败血症中S100a8/a9诱导的内皮功能障碍的机制尚不清楚.

研究的目的:

为了阐明在败血症期间S100a8/a9介导的内皮功能障碍背后的分子机制.
调查线粒体功能障碍和PANoptosis在这个过程中的作用.
为了将中性粒细胞中的S100A8/A9表达与败血症患者的临床结果相关联.

主要方法:

分析S100a8/a9表达及其对Ndufa3和Nrf1.9的影响.
评估线粒体复合体I功能,NAD+/Sirt1通路和线粒体动力学 (裂变/线粒体衰变).
对ZBP1介导的PANoptosis激活的评估.
使用scRNA-seq和散装RNA-seq进行中性粒细胞和患者数据分析.

主要成果:

高S100a8/a9表达通过Nrf1下调抑制Ndufa3,导致线粒体复合体I缺乏.
线粒体功能障碍导致NAD+依赖的Sirt1抑制,导致过度的线粒体分裂和线粒体衰减.
释放的mtDNA激活了内皮细胞中ZBP1依赖的PANoptosis.
S100A8/A9hi 中性粒细胞与循环内皮细胞计数相关,这是内皮损伤的标志物.
S100A8是预后不佳的败血症的一个独立风险因素.

结论:

S100a8/a9通过线粒体损伤和随后的PANoptosis驱动败血症诱导的内皮功能障碍.
中性粒细胞S100A8/A9水平和S100A8作为内皮损伤和败血症预后的潜在生物标志物.

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