LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury
LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury
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LncRNA H19 在视网膜缺血/再灌注损伤中引发小胶质细胞焦亡和神经元死亡 (IF:10.717)
DOI：
10.1038/s41418-019-0351-4
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发表时间：
2020-01-01
影响因子：
12.4
通讯作者：
Zhuo, Yehong
中科院分区：
文献类型：
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作者：
Wan, Peixing;Su, Wenru;Zhuo, Yehong
缺血再灌注（I/R）是一种常见的病理，当一个器官的血液供应中断，然后恢复。在再灌注过程中，免疫细胞和细胞因子介导炎症和组织损伤。然而，启动I/ r诱导炎症和驱动免疫细胞激活的机制在很大程度上仍然未知。在这项研究中，我们发现长链非编码RNA (lncRNA)-H19是I/ r诱导炎症的关键发病机制。我们发现，I/R增加lncRNA-H19表达，显著促进NLRP3/6炎性体失衡，导致小胶质细胞焦亡、细胞因子过量产生和神经元死亡。敲除lncRNA-H19可有效抑制这些损伤。具体而言，lncRNA-H19通过海绵miR-21促进PDCD4表达，并在缺血级联中形成竞争性内源性RNA网络（ceRNET）。LncRNA H19/miR21/PDCD4 ceRNET在体内可直接调控I/ r诱导的无菌炎症和神经元病变。因此，我们认为lncRNA-H19是I/R损伤分子和免疫途径中未知的危险信号，基于这些机制发现，抑制H19的药理学方法可能在不久的将来成为患者的治疗方式。
Ischemia-reperfusion (I/R) is a common pathology when the blood supply to an organ was disrupted and then restored. During the reperfusion process, inflammation and tissue injury were triggered, which were mediated by immunocytes and cytokines. However, the mechanisms initiating I/R-induced inflammation and driving immunocytes activation remained largely unknown. In this study, we identified long non-coding RNA (lncRNA)-H19 as the key onset of I/R-induced inflammation. We found that I/R increased lncRNA-H19 expression to significantly promote NLRP3/6 inflammasome imbalance and resulted in microglial pyroptosis, cytokines overproduction, and neuronal death. These damages were effectively inhibited by lncRNA-H19 knockout. Specifically, lncRNA-H19 functioned via sponging miR-21 to facilitate PDCD4 expression and formed a competing endogenous RNA network (ceRNET) in ischemic cascade. LncRNA H19/miR21/PDCD4 ceRNET can directly regulate I/R-induced sterile inflammation and neuronal lesion in vivo. We thus propose that lncRNA-H19 is a previously unknown danger signals in the molecular and immunological pathways of I/R injury, and pharmacological approaches to inhibit H19 seem likely to become treatment modalities for patients in the near future based on these mechanistic findings.