OPA1 modulates NLRP3 inflammasome activation and microglial-mediated neuroinflammation in neonatal hypoxic-ischemic brain injury

IF 2.5 4区医学 Q3 IMMUNOLOGY

Journal of neuroimmunology Pub Date : 2025-07-22 DOI:10.1016/j.jneuroim.2025.578701

Qingchen Lv , Fei Hong , Zhanyuan Sun , Haiyan Shen , Hongyi Lu , Ye Jin , Liming Mao , Lei Song

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引用次数: 0

Abstract

Background

Hypoxic-ischemic brain injury (HIBD) represents a primary cause of neurological impairment in neonates and is frequently associated with persistent cognitive and motor deficits. This study explores the regulatory function of optic atrophy 1 (OPA1) in modulating NLRP3 inflammasome-mediated neuroinflammation in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE), and evaluates the impact of the OPA1 inhibitor MYLS22 on neuroinflammatory responses and cerebral injury.

Methods

Neonatal rats were subjected to HIBD. Temporal expression patterns of OPA1 and inflammasome-associated proteins were assessed using Western blotting, immunofluorescence, and histopathological analyses. The influence of MYLS22 treatment on neuroinflammatory markers, brain pathology, and cognitive outcomes was also investigated.

Result

HIBD led to a marked reduction in long-form OPA1 (L-OPA1) expression and a concomitant increase in short-form OPA1 (S-OPA1). Activation of the NLRP3 inflammasome peaked between 24 and 48 h post-injury. Treatment with MYLS22 suppressed OPA1 expression in a dose-dependent manner, further enhancing inflammasome activation and aggravating brain injury, characterized by enlarged infarct volumes, increased edema, and impaired cognitive performance. Conversely, in vitro overexpression of L-OPA1 attenuated inflammasome activation and reduced microglial inflammation following ischemia/reperfusion insult, indicating a neuroprotective effect.

Conclusion

These findings demonstrate a pivotal role for OPA1 in controlling neuroinflammation and mitochondrial integrity in the context of HIE. Modulation of OPA1 expression or targeting inflammasome signaling may represent promising therapeutic strategies to alleviate neuroinflammatory injury and improve neurological outcomes in neonates.

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在新生儿缺氧缺血性脑损伤中，OPA1调节NLRP3炎性体激活和小胶质细胞介导的神经炎症

背景：缺氧缺血性脑损伤（HIBD）是新生儿神经功能损伤的主要原因，通常与持续的认知和运动缺陷有关。本研究探讨了视神经萎缩1 （OPA1）在新生儿缺氧缺血性脑病（HIE）大鼠模型中调节NLRP3炎症小体介导的神经炎症中的调节功能，并评价了OPA1抑制剂MYLS22对神经炎症反应和脑损伤的影响。方法对大鼠进行HIBD实验。使用Western blotting、免疫荧光和组织病理学分析评估OPA1和炎性小体相关蛋白的时间表达模式。我们还研究了MYLS22治疗对神经炎症标志物、脑病理和认知结果的影响。结果ibd导致长形OPA1 （L-OPA1）表达明显降低，同时短形OPA1 （S-OPA1）表达增加。NLRP3炎性小体的激活在损伤后24 - 48小时达到峰值。MYLS22以剂量依赖的方式抑制了OPA1的表达，进一步增强了炎性体的激活，加重了脑损伤，其特征是梗死体积增大、水肿增加和认知能力受损。相反，L-OPA1在体外过表达可减弱炎症小体的激活，减少缺血/再灌注损伤后的小胶质细胞炎症，表明其具有神经保护作用。结论在HIE的情况下，OPA1在控制神经炎症和线粒体完整性方面发挥了关键作用。调节OPA1表达或靶向炎性小体信号可能是缓解新生儿神经炎症损伤和改善神经预后的有希望的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of neuroimmunology 医学-免疫学

CiteScore

6.10

自引率

3.00%

发文量

154

审稿时长

37 days

期刊介绍： The Journal of Neuroimmunology affords a forum for the publication of works applying immunologic methodology to the furtherance of the neurological sciences. Studies on all branches of the neurosciences, particularly fundamental and applied neurobiology, neurology, neuropathology, neurochemistry, neurovirology, neuroendocrinology, neuromuscular research, neuropharmacology and psychology, which involve either immunologic methodology (e.g. immunocytochemistry) or fundamental immunology (e.g. antibody and lymphocyte assays), are considered for publication.