PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling.
PMN-derived netrin-1 attenuates cardiac ischemia-reperfusion injury via myeloid ADORA2B signaling.
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DOI：
10.1084/jem.20210008
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发表时间：
2021-06-07
期刊：
影响因子：
--
通讯作者：
Eltzschig HK
中科院分区：
文献类型：
--
作者：
Li J;Conrad C;Mills TW;Berg NK;Kim B;Ruan W;Lee JW;Zhang X;Yuan X;Eltzschig HK
心肌缺血再灌注损伤产生无菌炎症部位，中性粒细胞在这些部位被激活，导致心肌再灌注损伤。在此过程中，神经引导分子Netrin-1由激活的中性粒细胞释放，并通过激活髓系免疫细胞上表达的腺苷受体(ADORA2B)来抑制心肌炎症。以往的研究表明，神经导向分子Netrin-1在减轻心肌缺血再灌注损伤中起作用。然而，组织特异性来源和受体信号事件仍然难以捉摸。中性粒细胞是最先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的血液中Netrin-1水平升高，暴露在心肌缺血-再灌注中的小鼠也是如此。在Ntn1loxP/loxP Lyz2 Cre+小鼠中，发现有选择地增加了梗塞范围和肌钙蛋白水平，但在其他组织间隔中有条件地缺失netrin-1的小鼠中没有发现。使用中性粒细胞去除的活体研究发现，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受体在介导Netrin-1诱导的心脏保护中对嘌呤能信号事件的功能作用。这些发现表明，中性粒细胞衍生的Netrin-1通过髓样腺苷A2B信号通路在减轻心肌缺血再灌注损伤中发挥功能作用的自分泌信号环。
Myocardial ischemia-reperfusion injury generates sterile inflammation sites in which neutrophils are activated and cause myocardial reperfusion injury. During this event, the neuronal guidance molecule netrin-1 is released by activated neutrophils and dampens myocardial inflammation by activating adenosine receptors (ADORA2B) expressed on myeloid immune cells. 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.
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DOI：
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发表时间：
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