败血症
免疫系统
程序性细胞死亡
免疫学
脂多糖
医学
抗体
细胞凋亡
生物标志物
细胞
生物
遗传学
生物化学
作者
Marcel Doerflinger,Boris Reljić,Joseph Menassa,Christina Nedeva,Irvin Jose,Pierre Faou,Liana Mackiewicz,Ashley Mansell,Marc Pellegrini,Richard S. Hotchkiss,Hamsa Puthalakath
出处
期刊:FEBS Journal
[Wiley]
日期:2020-09-17
卷期号:288 (6): 1809-1821
被引量:13
摘要
Sepsis remains to be a major contributor to mortality in ICUs, and immune suppression caused by immune cell apoptosis determines the overall patient survival. However, diagnosis of sepsis‐induced lymphopenia remains problematic with no accurate prognostic techniques or biomarkers for cell death available. Developing reliable prognostic tools for sepsis‐mediated cell death is not only important for identifying patients at increased risk of immune suppression but also to monitor treatment progress of currently trialed immunotherapy strategies. We have previously shown an important role for endoplasmic reticulum stress (ER stress) in inducing sepsis‐mediated cell death and here report on the identification of a secreted form of the ER chaperone BiP (immunoglobulin binding protein) as a novel circulating prognostic biomarker for immune cell death and ER stress during sepsis. Using biochemical purification and mass spectrometry coupled with an established in vitro sepsis cell death assay, we identified BiP/Grp78 as a factor secreted by lipopolysaccharide‐activated macrophages that is capable of inducing cell death in target cells. Quantitative ELISA analysis showed significantly elevated levels of circulating BiP in mice undergoing polymicrobial sepsis, which was absent in Bim −/− mice that are protected from sepsis‐induced lymphopenia. Using blood serum from human sepsis patients, we could detect a significant difference in levels of secreted BiP in sepsis patients compared to nonseptic controls, suggesting that secreted circulating BiP could indeed be used as a prognostic marker that is directly correlative to immune cell death during sepsis.
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