中文摘要:
以前的研究表明神经元引导分子 netrin-1 有助于减轻心肌缺血再灌注损伤。然而,组织特异性来源和受体信号转导事件仍然难以捉摸。中性粒细胞是最早对缺血性损伤做出反应的细胞之一,可能与组织损伤或救援有关。我们发现心肌梗死患者血液中 netrin-1 水平升高,以及暴露于心肌缺血再灌注的小鼠。在 Ntn1loxP/loxP Lyz2 Cre+ 小鼠中发现选择性增加的梗死面积和肌钙蛋白水平,但在其他组织区室中条件性 netrin-1 缺失的小鼠中没有发现。使用中性粒细胞耗竭的体内研究确定,中性粒细胞是心肌损伤期间血液 netrin-1 升高的主要来源。最后,使用重组 netrin-1 治疗的药理学研究揭示了通过髓样腺苷 A2b 受体的嘌呤能信号事件在介导 netrin-1 诱导的心脏保护中的功能作用。这些发现表明,中性粒细胞来源的 netrin-1 在通过髓系腺苷 A2b 信号传导减轻心肌缺血再灌注损伤中具有功能作用的自分泌信号回路。
英文摘要:
Previous studies implicated the neuronal guidance molecule netrin-1 in attenuating myocardial ischemia-reperfusion injury. However, the tissue-specific sources and receptor signaling events remain elusive. Neutrophils are among the first cells responding to an ischemic insult and can be associated with tissue injury or rescue. We found netrin-1 levels were elevated in the blood of patients with myocardial infarction, as well as in mice exposed to myocardial ischemia-reperfusion. Selectively increased infarct sizes and troponin levels were found in Ntn1loxP/loxP Lyz2 Cre+ mice, but not in mice with conditional netrin-1 deletion in other tissue compartments. In vivo studies using neutrophil depletion identified neutrophils as the main source for elevated blood netrin-1 during myocardial injury. Finally, pharmacologic studies using treatment with recombinant netrin-1 revealed a functional role for purinergic signaling events through the myeloid adenosine A2b receptor in mediating netrin-1–elicited cardioprotection. These findings suggest an autocrine signaling loop with a functional role for neutrophil-derived netrin-1 in attenuating myocardial ischemia-reperfusion injury through myeloid adenosine A2b signaling.
论文信息:
论文题目: PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling
期刊名称:JEM- J Exp Med
时间期卷:J Exp Med (2021) 218 (6): e20210008.
在线时间:2021年4月23日
DOI: //doi.org/10.1084/jem.20210008
Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JEM:
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法:
JEM期刊缺血再灌注模型外周血单核巨噬细胞清除解决方案
Mice were given 100 µl/10 g body weight i.v. clodronate liposomes (Liposoma BV) 24 h before surgery to deplete monocytes and macrophages as described before . Control mice received liposomes only at the same time points.