Yao Meiling, Wang Xiaobei, Lin Hao, Shu Hui, Xu Zongtang, Tang Ling, Guo Wenyuan, Xu Pingyi
Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, China.
Inflammation. 2024 Dec 30. doi: 10.1007/s10753-024-02219-8.
Microglia, the central nervous system's primary immune cells, play a key role in the progression of cerebral ischemic stroke, particularly through their involvement in pyroptosis. The long non-coding RNA taurine up-regulated gene 1 (Tug1) is elevated during ischemic stroke and is critical in driving post-stroke neuroinflammation. However, the underlying molecular mechanisms remain unclear. This study explores the biological role of Tug1 and its potential mechanisms in regulating pyroptosis in microglia. We utilized an in vivo photothrombosis (PT) mice model and an in vitro oxygen-glucose deprivation and reperfusion (OGD/R) BV2 cell model to explore the mechanisms underlying ischemic stroke. Initially, we assessed the expression levels of Tug1 in the OGD/R model in vitro and the PT model in vivo. Subsequently, we investigated the impact of Tug1 on microglial pyroptosis by knocking down Tug1, silencing the PTEN-induced putative kinase 1 (Pink1) expression, and employing the mitophagy inhibitor mdivi-1. Tug1 exacerbated microglial pyroptosis by inhibiting mitophagy in both in vivo and in vitro models. The increase in mitophagy observed following Tug1 knockdown was reversed by either silencing Pink1 expression or using the mitophagy inhibitor mdivi-1. This reversal resulted in exacerbated pyroptosis and worsened neurological damage. Further mechanistic studies revealed that Tug1 knockdown significantly reduced microglial pyroptosis and alleviated neuronal damage by enhancing PINK1/Parkin-mediated mitophagy. For the first time, this study reveals that Tug1 promotes hypoxia-induced microglial pyroptosis by inhibiting PINK1/Parkin-mediated mitophagy, potentially providing a promising therapeutic target for ischemic inflammatory injury.
小胶质细胞是中枢神经系统的主要免疫细胞，在脑缺血性卒中的进展中起关键作用，特别是通过参与细胞焦亡。长链非编码RNA牛磺酸上调基因1（Tug1）在缺血性卒中期间升高，对驱动卒中后神经炎症至关重要。然而，其潜在的分子机制仍不清楚。本研究探讨Tug1的生物学作用及其调节小胶质细胞焦亡的潜在机制。我们利用体内光血栓形成（PT）小鼠模型和体外氧糖剥夺及再灌注（OGD/R）BV2细胞模型来探究缺血性卒中的潜在机制。首先，我们评估了体外OGD/R模型和体内PT模型中Tug1的表达水平。随后，我们通过敲低Tug1、沉默PTEN诱导的假定激酶1（Pink1）表达以及使用线粒体自噬抑制剂mdivi-1来研究Tug1对小胶质细胞焦亡的影响。在体内和体外模型中，Tug1均通过抑制线粒体自噬加剧小胶质细胞焦亡。Tug1敲低后观察到的线粒体自噬增加可通过沉默Pink1表达或使用线粒体自噬抑制剂mdivi-1来逆转。这种逆转导致细胞焦亡加剧和神经损伤恶化。进一步的机制研究表明，敲低Tug1可通过增强PINK1/Parkin介导的线粒体自噬显著减少小胶质细胞焦亡并减轻神经元损伤。本研究首次揭示，Tug1通过抑制PINK1/Parkin介导的线粒体自噬促进缺氧诱导的小胶质细胞焦亡，这可能为缺血性炎症损伤提供一个有前景的治疗靶点。
