RAGE interacts with the necroptotic protein RIPK3 and mediates transfusion-induced danger signal release.

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 in initiating cell death programmes such as necroptosis. Here, we demonstrate the role of in endothelial necroptosis, as deletion of duanyu1648 attenuates necroptotic cell death in response to TNFα, LPS or CpG-DNA. We show direct interaction of duanyu1648 with the critical mediator of necroptosis, Receptor Interacting 3 (RIPK3), during necroptosis. Furthermore, we observe decreased plasma High Mobility Group Box 1 (HMGB1) and RIPK3 levels in duanyu1648 deficient mice compared to WT mice post-transfusion, substantiating the role for duanyu1648 in transfusion-induced DAMP release in vivo. Collectively, these findings underscore duanyu1648 as an essential mediator of regulated necrosis and post-transfusion DAMP release. Further studies to understand the role of duanyu1648 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. © 2020 International Society of Blood Transfusion.

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