Department of Immunology, Infection and Immunity, Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin, China.
Autophagy. 2012 Nov;8(11):1621-7. doi: 10.4161/auto.21561. Epub 2012 Aug 9.
Autophagy is an important cellular recycling mechanism through self-digestion in responses to cellular stress such as starvation. Studies have shown that autophagy is involved in maintaining the homeostasis of the neural system during stroke. However, molecular mechanisms underlying neuronal autophagy in ischemic stroke remain poorly understood. Previously, we and others have shown that immune-related GTPase M (IRGM; termed IRGM1 in the mouse nomenclature) can regulate the survival of immune cells through autophagy in response to infections and autoimmune conditions. Here, using a permanent middle cerebral artery occlusion (pMCAO) mouse model, we found that IRGM1 was upregulated in the ischemic side of the brain, which was accompanied by a significant autophagic response. In contrast, neuronal autophagy was almost complete lost in Irgm1 knockout (KO) mice after pMCAO induction. In addition, the infarct volume in the Irgm1-KO pMCAO mice was significantly increased as compared to wild-type mice. Histological studies suggested that, at the early stage (within 24 h) of ischemia, the IRGM1-dependent autophagic response is associated with a protection of neurons from necrosis in the ischemic core but a promotion of neuronal apoptosis in the penumbra area. These data demonstrate a novel role of IRGM1 in regulating neuronal autophagy and survival during ischemic stroke.
自噬是一种重要的细胞回收机制，通过自我消化来应对细胞应激，如饥饿。研究表明，自噬参与了中风时神经系统的内稳态维持。然而，缺血性中风中神经元自噬的分子机制仍知之甚少。之前，我们和其他人已经表明，免疫相关 GTP 酶 M（IRGM；在小鼠命名法中称为 IRGM1）可以通过自噬来调节免疫细胞的存活，以应对感染和自身免疫状况。在这里，我们使用永久性大脑中动脉闭塞（pMCAO）小鼠模型，发现 IRGM1 在大脑缺血侧上调，同时伴随着明显的自噬反应。相比之下，在 pMCAO 诱导后，Irgm1 敲除（KO）小鼠中的神经元自噬几乎完全丧失。此外，与野生型小鼠相比，Irgm1-KO pMCAO 小鼠的梗死体积明显增加。组织学研究表明，在缺血的早期（24 小时内），IRGM1 依赖性自噬反应与保护缺血核心中的神经元免受坏死有关，但促进半影区中的神经元凋亡有关。这些数据表明 IRGM1 在调节缺血性中风期间神经元自噬和存活方面具有新的作用。
