内皮细胞 TREM-1 受体通过 SYK/β-连环蛋白信号通路调节小鼠脑出血后血脑屏障的完整性。

Endothelial TREM-1 receptor regulates the blood-brain barrier integrity after intracerebral hemorrhage in mice via SYK/β-catenin signaling.

机构信息

Department of Emergency, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, China.

Department of Pharmacy, Second Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.

出版信息

CNS Neurosci Ther. 2023 Nov;29(11):3228-3238. doi: 10.1111/cns.14255. Epub 2023 May 11.

BACKGROUND

Intracerebral hemorrhage (ICH) is a high mortality and disability stroke subtype. Destruction of the blood-brain barrier (BBB) is a crucial contributor to brain edema and neurological deficit after ICH. Triggering receptor expressed on myeloid cells 1 (TREM-1) has been reported to be expressed in endothelial cells, but its role in ICH remains unclear. This study aims to evaluate the role of TREM-1 on BBB permeability after ICH in mice.

METHODS

Two hundred and forty-two CD1 mice were used in this study. The ICH model was established by collagenase injection. LP17 was administered intranasally at 2 or 8 h after ICH to inhibit TREM-1. To explore the underlying mechanism, SYK activation CRISPR was administered intracerebroventricularly with LP17, and Anti-mouse TREM-1 rat IgG2a (a specific TREM-1 agonist) was injected intracerebroventricularly with R406 (a specific SYK inhibitor) intraperitoneally. Neurobehavioral outcome, brain water content, BBB permeability, and protein expression were evaluated.

RESULTS

The expression level of the TREM-1 receptor increased rapidly as early as 6 h after ICH, and it was mainly expressed on the endotheliocytes in the neurovascular unit. Early and delayed administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 h after ICH. LP17 reduced the BBB permeability by increasing β-catenin, claudin-5 and ZO-1 expression. Furthermore, SYK activation CRISPR abolished the beneficial effect of LP17 on the expression of the above junction molecules. Meanwhile, R406 reversed the impact of the TREM-1 activator on the downregulation of β-catenin, claudin-5 and ZO-1 expression.

CONCLUSIONS

This study demonstrated that TREM-1 deteriorated BBB permeability via modulating the expression of interendothelial junction molecules after ICH, and this regulation is partly mediated by the SYK/β-catenin signaling pathway.

背景

脑出血（ICH）是一种高死亡率和高致残率的卒中亚型。血脑屏障（BBB）的破坏是脑出血后脑水肿和神经功能缺损的关键因素。髓样细胞触发受体 1（TREM-1）已被报道在内皮细胞中表达，但它在 ICH 中的作用尚不清楚。本研究旨在评估 TREM-1 在小鼠脑出血后 BBB 通透性中的作用。

方法

本研究使用了 242 只 CD1 小鼠。通过胶原酶注射建立 ICH 模型。ICH 后 2 或 8 小时，通过鼻内给予 LP17 抑制 TREM-1。为了探讨潜在的机制，用 LP17 给予 SYK 激活 CRISPR，并用 R406（一种特异性 SYK 抑制剂）腹腔内给予抗小鼠 TREM-1 大鼠 IgG2a（一种特异性 TREM-1 激动剂）。评估神经行为学结果、脑水含量、BBB 通透性和蛋白表达。

结果

TREM-1 受体的表达水平在脑出血后 6 小时内迅速增加，并且主要在内皮细胞中表达。早期和晚期给予 LP17 可显著降低脑出血后 24 小时的脑水肿并改善神经行为学结果。LP17 通过增加β-连环蛋白、紧密连接蛋白 5 和 ZO-1 的表达来降低 BBB 通透性。此外，SYK 激活 CRISPR 消除了 LP17 对上述连接分子表达的有益作用。同时，R406 逆转了 TREM-1 激活剂对β-连环蛋白、紧密连接蛋白 5 和 ZO-1 表达下调的影响。