Department of Pediatric, Affiliated Hospital of Nantong University, Nantong 226001, China.
Department of Human Anatomy, School of Medicine, Nantong University, Nantong 226001, China.
Crit Rev Immunol. 2025;45(1):55-64. doi: 10.1615/CritRevImmunol.2024053554.
Hypoxic-ischemic encephalopathy (HIE) is a perinatal injury caused by cerebral hypoxia and reduced blood perfusion. Microglia activation-induced neuroinflammatory injury is a leading cause of neuron loss and brain injury. Efficient treatment strategies are still required further investigation. Our study is aimed to investigate the role of IRE1-XBP1 inhibitor 4μ8С in HIE. Rat pups (7 d) were used to establish HIE model using unilateral carotid artery ligation and hypoxia. A series of experiments including Western blot, Morris water maze test, TTC staining, RT-qPCR, TUNEL staining, and immunofluorescence staining were operated to evaluate the role of 4μ8С in HIE. 4μ8С treatment effectively reduced phosphorylated IRElα and XBP1 protein levels. 4μ8С treatment improves cognition and learning abilities of HIE rats. 4μ8С treatment alleviated brain infarction and cell apoptosis in HIE rats. 4μ8С treatment inhibited NLRP3 inflammasome activation-mediated microglia activation and inflammatory response. In conclusion, 4μ8С suppressed microglia and NLRP3 inflammasome activation by inactivating IRE1/XBP1 axis during HIE development, which revealed IRE1α inhibition as a novel mechanism for neuron protection.
缺氧缺血性脑病（HIE）是一种围产期损伤，由脑缺氧和血液灌注减少引起。小胶质细胞激活诱导的神经炎症损伤是神经元丧失和脑损伤的主要原因。仍需要进一步研究有效的治疗策略。我们的研究旨在探讨 IRE1-XBP1 抑制剂 4μ8C 在 HIE 中的作用。使用单侧颈总动脉结扎和缺氧建立 7 天大的大鼠幼仔 HIE 模型。进行了一系列实验，包括 Western blot、Morris 水迷宫测试、TTC 染色、RT-qPCR、TUNEL 染色和免疫荧光染色，以评估 4μ8C 在 HIE 中的作用。4μ8C 治疗有效降低了磷酸化 IRElα 和 XBP1 蛋白水平。4μ8C 治疗改善了 HIE 大鼠的认知和学习能力。4μ8C 治疗减轻了 HIE 大鼠的脑梗死和细胞凋亡。4μ8C 治疗抑制了 NLRP3 炎性小体激活介导的小胶质细胞激活和炎症反应。总之，4μ8C 通过在 HIE 发展过程中失活 IRE1/XBP1 轴来抑制小胶质细胞和 NLRP3 炎性小体的激活，这揭示了 IRE1α 抑制作为神经元保护的一种新机制。
