The IRE1-XBP1 axis regulates NLRP3 inflammasome-mediated microglia activation in hypoxic ischemic encephalopathy

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.