TREM2 activation reduces white matter injury via PI3K/Akt/GSK-3β signalling after intracerebral haemorrhage

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2025-02-18 DOI:10.1111/bph.17475

Yuan Zhang, You Shi, Lin Wang, Zhao Li, Yingwen Wang, Jin Yan, Xiaochuan Sun, Qing Luo, Lin Li

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引用次数: 0

Abstract

Background

White matter injury (WMI) considerably exacerbates the prognosis following intracerebral haemorrhage (ICH). While the triggering receptor on myeloid cells 2 (TREM2) is recognized for its neuroprotective roles in a range of neurological disorders through the modulation of neuroinflammation, phagocytosis, promoting cell survival, its specific function in WMI after ICH has yet to be fully elucidated.

Methods

This study involved inducing ICH in mice through autologous blood injection. Neurological functions were tested via behavioural assessments and electrophysiological recordings. WMI was examined using immunofluorescence, Luxol fast blue staining, MRI and transmission electron microscopy. Microglia were isolated and analysed using real-time polymerase chain reaction (PCR). Microglia depletion was achieved with PLX3397, primary cultures of microglia and oligodendrocytes were investigated.

Results

The activation of TREM2 resulted in improved neurological outcomes after ICH, correlated with reduced WMI, demonstrated by decreased white matter loss in the corpus striatum, reduced damage to the nodes of Ranvier, and better preservation of myelin and white matter tract integrity. These neuroprotective effects were attributed to changes in microglial states mediated via the PI3K/Akt/GSK-3β signalling pathway. However, the neuroprotective advantages conferred by TREM2 activation were negated in TREM2 KO mice, either through microglia depletion or inhibition of PI3K.

Conclusions

This research is the first to illustrate that TREM2 activation mitigates WMI following ICH through a microglia-dependent mechanism involving the PI3K/Akt/GSK-3β pathway. TREM2 represents a potential therapeutic target for ICH.

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脑出血后，TREM2激活通过PI3K/Akt/GSK-3β信号通路减少白质损伤。

背景：脑白质损伤（WMI）显著加重脑出血（ICH）后的预后。髓样细胞2上的触发受体（TREM2）通过调节神经炎症、吞噬、促进细胞存活，在一系列神经系统疾病中发挥神经保护作用，但其在脑出血后WMI中的具体功能尚未完全阐明。方法：采用自体血液注射法诱导小鼠脑出血。通过行为评估和电生理记录测试神经功能。采用免疫荧光、Luxol快速蓝染色、MRI和透射电镜检测WMI。采用实时聚合酶链反应（real-time polymerase chain reaction， PCR）对小胶质细胞进行分离和分析。用PLX3397实现小胶质细胞耗竭，研究了小胶质细胞和少突胶质细胞的原代培养。结果：TREM2的激活改善了脑出血后的神经系统预后，与减少的WMI相关，表现为纹状体白质损失减少，Ranvier淋巴结损伤减少，髓鞘和白质束完整性得到更好的保存。这些神经保护作用归因于PI3K/Akt/GSK-3β信号通路介导的小胶质细胞状态的改变。然而，TREM2激活所赋予的神经保护优势在TREM2 KO小鼠中被否定，通过小胶质细胞缺失或PI3K的抑制。结论：本研究首次阐明TREM2激活通过涉及PI3K/Akt/GSK-3β途径的小胶质细胞依赖机制减轻ICH后的WMI。TREM2是脑出血的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.