Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis
Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis
复制标题
小胶质细胞 lnc-U90926 通过 MDH2/CXCL2 轴促进缺血性中风中的中性粒细胞浸润
DOI：
10.1016/j.ymthe.2021.04.025
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发表时间：
2021-09-01
影响因子：
12.4
通讯作者：
Xu, Yun
中科院分区：
文献类型：
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作者：
Chen, Jian;Jin, Jiali;Xu, Yun
研究表明，长链非编码RNA（lncRNA）表达异常与缺血性卒中的发病机制有关。然而，lncRNA在卒中后小胶质细胞活化中的潜在作用在很大程度上仍然未知。在这里，我们发现lncRNA-U90926在体内和体外暴露于缺血/再灌注的小胶质细胞中显著增加。此外，腺病毒相关病毒（AAV）介导的小胶质细胞U90926沉默减轻了实验性中风小鼠的神经功能缺损并减少了梗死体积。小胶质细胞U90926基因敲减可减少中性粒细胞向缺血损伤部位的浸润，其机制可能与下调C-X-C基序配体2（CXCL 2）有关。机制上，U90926直接结合苹果酸脱氢酶2（MDH 2），竞争性抑制MDH 2与CXCL 2 30非翻译区（UTR）的结合，从而保护免受MDH 2介导的CXCL 2 mRNA的衰变。总之，我们的研究表明，小胶质细胞U90926通过促进中性粒细胞浸润而加重缺血性脑损伤，这表明U90926可能是缺血性脑卒中的潜在生物标志物和治疗靶点。
Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 30 untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.