Allergy, Pulmonary and Critical Care Division, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Vox Sang. 2020 Nov;115(8):729-734. doi: 10.1111/vox.12946. Epub 2020 Jul 7.
RBC transfusion is associated with increased morbidity and mortality in critically ill patients. Endothelial cell necroptosis and subsequent damage-associated molecular pattern (DAMP) release has been identified as a mechanism of injury following RBC transfusion. Mounting evidence implicates the pro-inflammatory pattern recognition receptor, Receptor for Advanced Glycation End Products (RAGE), in initiating cell death programmes such as necroptosis. Here, we demonstrate the role of RAGE in endothelial necroptosis, as deletion of RAGE attenuates necroptotic cell death in response to TNFα, LPS or CpG-DNA. We show direct interaction of RAGE with the critical mediator of necroptosis, Receptor Interacting Protein Kinase 3 (RIPK3), during necroptosis. Furthermore, we observe decreased plasma High Mobility Group Box 1 (HMGB1) and RIPK3 levels in RAGE deficient mice compared to WT mice post-transfusion, substantiating the role for RAGE in transfusion-induced DAMP release in vivo. Collectively, these findings underscore RAGE as an essential mediator of regulated necrosis and post-transfusion DAMP release. Further studies to understand the role of RAGE and the necroptotic pathway in transfusion-induced organ injury may offer key targets to mitigate transfusion-related risks, including the risk of ARDS, in susceptible hosts.
红细胞输注与危重症患者的发病率和死亡率增加有关。已经确定，红细胞输注后内皮细胞坏死和随后的损伤相关分子模式（DAMP）释放是损伤的一种机制。越来越多的证据表明，促炎模式识别受体，晚期糖基化终产物受体（RAGE），在启动细胞死亡程序（如坏死）中起作用。在这里，我们证明了 RAGE 在血管内皮细胞坏死中的作用，因为 RAGE 的缺失可减轻 TNFα、LPS 或 CpG-DNA 引起的坏死性细胞死亡。我们在坏死过程中观察到 RAGE 与坏死关键介质受体相互作用蛋白激酶 3（RIPK3）的直接相互作用。此外，与 WT 小鼠相比，RAGE 缺陷型小鼠在输血后血浆高迁移率族蛋白 B1（HMGB1）和 RIPK3 水平降低，这证实了 RAGE 在体内输血诱导的 DAMP 释放中的作用。总之，这些发现强调了 RAGE 作为调节性坏死和输血后 DAMP 释放的重要介质。进一步研究 RAGE 和坏死途径在输血诱导的器官损伤中的作用，可能为减轻输血相关风险提供关键靶点，包括易感宿主中 ARDS 的风险。
