HBO-PC Reprograms Neuroimmune Metabolism Through Disruption of the LRG1-HIF-1α-IL-6-STAT3 Amplification Loop Attenuates Pyroptosis and Ischemia-Reperfusion Injury.

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2026-05-01 DOI:10.1002/cns.70907

Wenying Lv, Junzhe Lv, Kexin Xiong, Shunshun Yuan, Jingyao Yang, Dazhi Guo

{"title":"HBO-PC Reprograms Neuroimmune Metabolism Through Disruption of the LRG1-HIF-1α-IL-6-STAT3 Amplification Loop Attenuates Pyroptosis and Ischemia-Reperfusion Injury.","authors":"Wenying Lv, Junzhe Lv, Kexin Xiong, Shunshun Yuan, Jingyao Yang, Dazhi Guo","doi":"10.1002/cns.70907","DOIUrl":null,"url":null,"abstract":"Background: Neuroinflammation and pyroptosis driven by excessive microglial activation play key roles in cerebral ischemia-reperfusion injury (CIRI). Hyperbaric oxygen preconditioning (HBO-PC) exhibits neuroprotective effects, but its mechanisms remain unclear. Leucine-rich α-2-glycoprotein 1 (LRG1) is implicated in CIRI pathology, yet whether HBO-PC modulates neuroinflammation and pyroptosis via LRG1 is unknown.Methods: A mouse CIRI model was generated by middle cerebral artery occlusion. HBO-PC and LRG1 siRNA knockdown were applied. Neurological function and molecular changes were evaluated.Results: HBO-PC reduced infarct volume and improved neurological outcomes, while downregulating LRG1 in neurons and microglia. LRG1 promoted HIF-1α accumulation by inhibiting prolyl hydroxylase activity, leading to caspase-3-dependent GSDME cleavage and pyroptosis. Released IL-6 activated STAT3, which further transcriptionally upregulated LRG1, forming a self-amplifying HIF-1α/GSDME/IL-6/STAT3 loop. HBO-PC disrupted this circuit and shifted microglia toward an anti-inflammatory phenotype.Conclusion: HBO-PC protects against CIRI by breaking the LRG1-HIF-1α-IL-6-STAT3 feedback loop, thereby attenuating pyroptosis and neuroinflammation while promoting anti-inflammatory microglial polarization. LRG1 represents a promising therapeutic target in ischemic brain injury.","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"32 5","pages":"e70907"},"PeriodicalIF":5.0000,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127231/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cns.70907","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Neuroinflammation and pyroptosis driven by excessive microglial activation play key roles in cerebral ischemia-reperfusion injury (CIRI). Hyperbaric oxygen preconditioning (HBO-PC) exhibits neuroprotective effects, but its mechanisms remain unclear. Leucine-rich α-2-glycoprotein 1 (LRG1) is implicated in CIRI pathology, yet whether HBO-PC modulates neuroinflammation and pyroptosis via LRG1 is unknown.

Methods: A mouse CIRI model was generated by middle cerebral artery occlusion. HBO-PC and LRG1 siRNA knockdown were applied. Neurological function and molecular changes were evaluated.

Results: HBO-PC reduced infarct volume and improved neurological outcomes, while downregulating LRG1 in neurons and microglia. LRG1 promoted HIF-1α accumulation by inhibiting prolyl hydroxylase activity, leading to caspase-3-dependent GSDME cleavage and pyroptosis. Released IL-6 activated STAT3, which further transcriptionally upregulated LRG1, forming a self-amplifying HIF-1α/GSDME/IL-6/STAT3 loop. HBO-PC disrupted this circuit and shifted microglia toward an anti-inflammatory phenotype.

Conclusion: HBO-PC protects against CIRI by breaking the LRG1-HIF-1α-IL-6-STAT3 feedback loop, thereby attenuating pyroptosis and neuroinflammation while promoting anti-inflammatory microglial polarization. LRG1 represents a promising therapeutic target in ischemic brain injury.

查看原文本刊更多论文

HBO-PC通过破坏LRG1-HIF-1α-IL-6-STAT3扩增环重编程神经免疫代谢，减轻焦亡和缺血再灌注损伤。

背景：小胶质细胞过度激活导致的神经炎症和焦亡在脑缺血再灌注损伤（CIRI）中起关键作用。高压氧预处理（HBO-PC）具有神经保护作用，但其机制尚不清楚。富亮氨酸α-2糖蛋白1 （LRG1）参与CIRI病理，但HBO-PC是否通过LRG1调节神经炎症和焦亡尚不清楚。方法：建立大脑中动脉闭塞小鼠CIRI模型。应用HBO-PC和LRG1 siRNA敲除。评估神经功能和分子变化。结果：HBO-PC减少了梗死体积，改善了神经预后，同时下调了神经元和小胶质细胞中的LRG1。LRG1通过抑制脯氨酸羟化酶活性促进HIF-1α积累，导致caspase-3依赖性GSDME裂解和焦亡。释放IL-6激活STAT3，进一步上调LRG1的转录水平，形成一个自我扩增的HIF-1α/GSDME/IL-6/STAT3环。HBO-PC破坏了这一回路，使小胶质细胞转向抗炎表型。结论：HBO-PC通过破坏LRG1-HIF-1α-IL-6-STAT3反馈回路，从而减轻焦亡和神经炎症，促进抗炎小胶质细胞极化。LRG1是缺血性脑损伤的一个有前景的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.