Abstract：
OBJECTIVE: Acute myocardial infarction (AMI) is a leading cause of mortality. Neutrophils penetrate injured heart tissue during AMI or ischemia-reperfusion (I/R) injury and produce inflammatory factors, chemokines, and extracellular traps that exacerbate heart injury. Inhibition of the TRAIL-DR5 pathway has been demonstrated to alleviate cardiac ischemia-reperfusion injury in a leukocyte-dependent manner. However, it remains unknown whether TRAIL-DR5 signaling is involved in regulating neutrophil extracellular traps (NETs) release.
METHODS: This study used various models to examine the effects of activating the TRAIL-DR5 pathway with soluble mouse TRAIL protein and inhibiting the TRAIL-DR5 signaling pathway using DR5 knockout mice or mDR5-Fc fusion protein on NETs formation and cardiac injury. The models used included a co-culture model involving bone marrow-derived neutrophils and primary cardiomyocytes and a model of myocardial I/R in mice.
RESULTS: NETs formation is suppressed by TRAIL-DR5 signaling pathway inhibition, which can lessen cardiac I/R injury. This intervention reduces the release of adhesion molecules and chemokines, resulting in decreased neutrophil infiltration and inhibiting NETs production by downregulating PAD4 in neutrophils.
CONCLUSIONS: This work clarifies how the TRAIL-DR5 signaling pathway regulates the neutrophil response during myocardial I/R damage, thereby providing a scientific basis for therapeutic intervention targeting the TRAIL-DR5 signaling pathway in myocardial infarction.
METHODS: This study used various models to examine the effects of activating the TRAIL-DR5 pathway with soluble mouse TRAIL protein and inhibiting the TRAIL-DR5 signaling pathway using DR5 knockout mice or mDR5-Fc fusion protein on NETs formation and cardiac injury. The models used included a co-culture model involving bone marrow-derived neutrophils and primary cardiomyocytes and a model of myocardial I/R in mice.
RESULTS: NETs formation is suppressed by TRAIL-DR5 signaling pathway inhibition, which can lessen cardiac I/R injury. This intervention reduces the release of adhesion molecules and chemokines, resulting in decreased neutrophil infiltration and inhibiting NETs production by downregulating PAD4 in neutrophils.
CONCLUSIONS: This work clarifies how the TRAIL-DR5 signaling pathway regulates the neutrophil response during myocardial I/R damage, thereby providing a scientific basis for therapeutic intervention targeting the TRAIL-DR5 signaling pathway in myocardial infarction.
摘要：
目的：急性心肌梗死（AMI）是死亡的主要原因。中性粒细胞在AMI或缺血再灌注(I/R)损伤期间穿透受损的心脏组织并产生炎症因子,趋化因子,和加剧心脏损伤的细胞外诱捕网。已经证明TRAIL-DR5途径的抑制以白细胞依赖性方式减轻心脏缺血-再灌注损伤。然而,目前尚不清楚TRAIL-DR5信号是否参与调节中性粒细胞胞外捕获网(NETs)的释放.
方法：本研究使用各种模型来检查用可溶性小鼠TRAIL蛋白激活TRAIL-DR5通路并使用DR5敲除小鼠或mDR5-Fc融合蛋白抑制TRAIL-DR5信号通路对NETs形成和心脏损伤的影响。所使用的模型包括涉及骨髓来源的嗜中性粒细胞和原代心肌细胞的共培养模型和小鼠中的心肌I/R模型。
结果：NETs的形成受到TRAIL-DR5信号通路抑制的抑制，这可以减轻心脏I/R损伤。这种干预减少了粘附分子和趋化因子的释放，导致中性粒细胞浸润减少，并通过下调中性粒细胞中的PAD4来抑制NETs的产生。
结论：这项工作阐明了TRAIL-DR5信号通路如何在心肌I/R损伤期间调节中性粒细胞反应，从而为心肌梗死中靶向TRAIL-DR5信号通路的治疗干预提供科学依据。
方法：本研究使用各种模型来检查用可溶性小鼠TRAIL蛋白激活TRAIL-DR5通路并使用DR5敲除小鼠或mDR5-Fc融合蛋白抑制TRAIL-DR5信号通路对NETs形成和心脏损伤的影响。所使用的模型包括涉及骨髓来源的嗜中性粒细胞和原代心肌细胞的共培养模型和小鼠中的心肌I/R模型。
结果：NETs的形成受到TRAIL-DR5信号通路抑制的抑制，这可以减轻心脏I/R损伤。这种干预减少了粘附分子和趋化因子的释放，导致中性粒细胞浸润减少，并通过下调中性粒细胞中的PAD4来抑制NETs的产生。
结论：这项工作阐明了TRAIL-DR5信号通路如何在心肌I/R损伤期间调节中性粒细胞反应，从而为心肌梗死中靶向TRAIL-DR5信号通路的治疗干预提供科学依据。
