Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization.
Noncanonical contribution of microglial transcription factor NR4A1 to post-stroke recovery through TNF mRNA destabilization.
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DOI：
10.1371/journal.pbio.3002199
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发表时间：
2023-07
期刊：
影响因子：
9.8
通讯作者：
Xu, Yun
中科院分区：
文献类型：
--
作者：
Liu, Pinyi;Chen, Yan;Zhang, Zhi;Yuan, Zengqiang;Sun, Jian-Guang;Xia, Shengnan;Cao, Xiang;Chen, Jian;Zhang, Cun-Jin;Chen, Yanting;Zhan, Hui;Jin, Yuexinzi;Bao, Xinyu;Gu, Yue;Zhang, Meijuan;Xu, Yun
小胶质细胞介导的神经炎症与多种神经系统疾病有关，包括缺血性中风，但预防非应激性炎症的内源性机制仍不清楚。转录因子核受体亚家族 4 A 组成员 1 (NR4A1) 在巨噬细胞和小胶质细胞中的抗炎作用先前已被鉴定。然而，NR4A1 如何限制非应激炎症的内源机制仍然难以捉摸。在这里，我们观察到 NR4A1 在激活的小胶质细胞的细胞质中上调，并定位于加工体（P 体）。此外，我们发现细胞质 NR4A1 作为 RNA 结合蛋白 (RBP) 发挥作用，以 N6-甲基腺苷 (m6A) 依赖性方式直接结合 Tnf mRNA 并使其不稳定。值得注意的是，在缺血性中风小鼠模型中，Nr4a1 的条件性小胶质细胞缺失会提高 Tnf 表达并使结果恶化，在这种情况下，小胶质细胞细胞质中的 NR4A1 表达被显着诱导。因此，我们的研究阐明了 NR4A1 转录后调节小胶质细胞中 Tnf 表达并决定中风结果的新机制。小胶质细胞介导的神经炎症与缺血性中风等神经系统疾病有关，但预防非应激性炎症的机制尚不清楚。这项研究揭示了经典转录因子 NR4A1 作为一种 RNA 结合蛋白在小胶质细胞中具有新的作用，它定位于加工体，以破坏促炎转录物的稳定性并减轻缺血性脑损伤。
Microglia-mediated neuroinflammation is involved in various neurological diseases, including ischemic stroke, but the endogenous mechanisms preventing unstrained inflammation is still unclear. The anti-inflammatory role of transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) in macrophages and microglia has previously been identified. However, the endogenous mechanisms that how NR4A1 restricts unstrained inflammation remain elusive. Here, we observed that NR4A1 is up-regulated in the cytoplasm of activated microglia and localizes to processing bodies (P-bodies). In addition, we found that cytoplasmic NR4A1 functions as an RNA-binding protein (RBP) that directly binds and destabilizes Tnf mRNA in an N6-methyladenosine (m6A)-dependent manner. Remarkably, conditional microglial deletion of Nr4a1 elevates Tnf expression and worsens outcomes in a mouse model of ischemic stroke, in which case NR4A1 expression is significantly induced in the cytoplasm of microglia. Thus, our study illustrates a novel mechanism that NR4A1 posttranscriptionally regulates Tnf expression in microglia and determines stroke outcomes. Microglia-mediated neuroinflammation is involved in neurological diseases such as ischemic stroke, but the mechanisms that prevent unstrained inflammation are unclear. This study reveals that the canonical transcription factor NR4A1 has a novel role in microglia as an RNA-binding protein that localizes to processing bodies to destabilize pro-inflammatory transcript and alleviate ischemic brain injury.
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