The IRE1-XBP1 Axis Regulates NLRP3 Inflammasome-Mediated Microglia Activation in Hypoxic Ischemic Encephalopathy.

IF 0.8 4区医学 Q4 IMMUNOLOGY Critical Reviews in Immunology Pub Date : 2025-01-01 DOI:10.1615/CritRevImmunol.2024053554

Qun Cai, Liyuan Shen, Xiaoqun Zhang, Zhijun Zhang, Ting Wang

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Abstract

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.

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IRE1-XBP1轴调控缺氧缺血性脑病中NLRP3炎性小体介导的小胶质细胞激活。

缺氧缺血性脑病（HIE）是一种由脑缺氧和血液灌注减少引起的围产期损伤。小胶质细胞激活引起的神经炎症损伤是神经元丢失和脑损伤的主要原因。有效的治疗策略仍需进一步研究。我们的研究旨在探讨IRE1-XBP1抑制剂4μ8С在HIE中的作用。采用单侧颈动脉结扎和缺氧的方法建立HIE大鼠仔（7 d）模型。通过Western blot、Morris水迷宫实验、TTC染色、RT-qPCR、TUNEL染色、免疫荧光染色等一系列实验评价4μ8С在HIE中的作用。4μ8С治疗有效降低磷酸化IRElα和XBP1蛋白水平。4μ8С治疗可改善HIE大鼠的认知和学习能力。4μ8С治疗可减轻HIE大鼠脑梗死和细胞凋亡。4μ8С治疗抑制NLRP3炎性小体激活介导的小胶质细胞激活和炎症反应。综上所述，4μ8С在HIE发育过程中通过灭活IRE1/XBP1轴抑制小胶质细胞和NLRP3炎性体的激活，揭示了IRE1α抑制是一种新的神经元保护机制。

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来源期刊

Critical Reviews in Immunology 医学-免疫学

CiteScore

2.60

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Immunology covers a broad spectrum of investigations at the genes, molecular, cellular, organ and system levels to reveal defense mechanisms against pathogens as well as protection against tumors and autoimmune diseases. The great advances in immunology in recent years make this field one of the most dynamic and rapidly growing in medical sciences. Critical ReviewsTM in Immunology (CRI) seeks to present a balanced overview of contemporary adaptive and innate immune responses related to autoimmunity, tumor, microbe, transplantation, neuroimmunology, immune regulation and immunotherapy from basic to translational aspects in health and disease. The articles that appear in CRI are mostly obtained by invitations to active investigators. But the journal will also consider proposals from the scientific community. Interested investigators should send their inquiries to the editor before submitting a manuscript.