HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation
HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation
复制标题
DOI：
10.1002/glia.24380
复制
发表时间：
2023-05
期刊：
影响因子：
6.2
通讯作者：
K. Rosiewicz;B. Muinjonov;Séverine Kunz;H. Radbruch;Jessy Chen;R. Jüttner;Janis Kerkering;Julia Ucar;Tadhg Crowley;B. Wielockx;Friedemann Paul;Marlen Alisch;Volker Siffrin
中科院分区：
文献类型：
--
作者：
K. Rosiewicz;B. Muinjonov;Séverine Kunz;H. Radbruch;Jessy Chen;R. Jüttner;Janis Kerkering;Julia Ucar;Tadhg Crowley;B. Wielockx;Friedemann Paul;Marlen Alisch;Volker Siffrin
星形胶质细胞构成血脑屏障（BBB）的实质边界，调节可溶性和细胞元素的交换，对神经元代谢支持至关重要。因此，星形胶质细胞严重影响神经网络的完整性。在缺氧情况下，星形胶质细胞上调转录程序，该转录程序已被证明在几种神经系统疾病模型中增强神经保护作用。我们通过删除氧传感器、HIF脯氨酸羟化酶结构域2和3（博士2/3），研究了具有星形胶质细胞特异性缺氧反应程序激活的转基因小鼠。我们在实验性自身免疫性脑脊髓炎（EAE）出现临床症状后诱导星形细胞Phd2/3缺失，导致大量免疫细胞浸润介导的疾病恶化。我们发现博士2/3‐ko星形胶质细胞虽然表达神经保护特征，但在血管内皮生长因子α （Vegf‐a）表达诱导下，表现出间隙连接蛋白43 （Cx43）的逐渐丧失。这些结果提供了星形胶质细胞生物学的机制见解，它们在缺氧状态和慢性炎症性中枢神经系统疾病中的关键作用。
Astrocytes constitute the parenchymal border of the blood–brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte‐specific activation of the hypoxia‐response program by deleting the oxygen sensors, HIF prolyl‐hydroxylase domains 2 and 3 (Phd2/3). We induced astrocytic Phd2/3 deletion after onset of clinical signs in experimental autoimmune encephalomyelitis (EAE) that led to an exacerbation of the disease mediated by massive immune cell infiltration. We found that Phd2/3‐ko astrocytes, though expressing a neuroprotective signature, exhibited a gradual loss of gap‐junctional Connexin‐43 (Cx43), which was induced by vascular endothelial growth factor‐alpha (Vegf‐a) expression. These results provide mechanistic insights into astrocyte biology, their critical role in hypoxic states, and in chronic inflammatory CNS diseases.