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颈动脉血管狭窄导致血脑屏障损伤和神经炎症。

Carotid artery vascular stenosis causes the blood-CSF barrier damage and neuroinflammation.

机构信息

Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, 116027, Liaoning, China.

Department of Neurology, University of Pittsburgh Medical Center, 7016 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15213, USA.

出版信息

J Neuroinflammation. 2024 Sep 10;21(1):220. doi: 10.1186/s12974-024-03209-1.

DOI:10.1186/s12974-024-03209-1
PMID:39256783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11385148/
Abstract

BACKGROUND

The choroid plexus (ChP) helps maintain the homeostasis of the brain by forming the blood-CSF barrier via tight junctions (TJ) at the choroid plexus epithelial cells, and subsequently preventing neuroinflammation by restricting immune cells infiltration into the central nervous system. However, whether chronic cerebral hypoperfusion causes ChP structural damage and blood-CSF barrier impairment remains understudied.

METHODS

The bilateral carotid stenosis (BCAS) model in adult male C57BL/6 J mice was used to induce cerebral hypoperfusion, a model for vascular contributions to cognitive impairment and dementia (VCID). BCAS-mediated changes of the blood-CSF barrier TJ proteins, apical secretory Na-K-Cl cotransporter isoform 1 (NKCC1) protein and regulatory serine-threonine kinases SPAK, and brain infiltration of myeloid-derived immune cells were assessed.

RESULTS

BCAS triggered dynamic changes of TJ proteins (claudin 1, claudin 5) accompanied with stimulation of SPAK-NKCC1 complex and NF-κB in the ChP epithelial cells. These changes impacted the integrity of the blood-CSF barrier, as evidenced by ChP infiltration of macrophages/microglia, neutrophils and T cells. Importantly, pharmacological blockade of SPAK with its potent inhibitor ZT1a in BCAS mice attenuated brain immune cell infiltration and improved cognitive neurological function.

CONCLUSIONS

BCAS causes chronic ChP blood-CSF damage and immune cell infiltration. Our study sheds light on the SPAK-NKCC1 complex as a therapeutic target in neuroinflammation.

摘要

背景

脉络丛（ChP）通过脉络丛上皮细胞的紧密连接（TJ）形成血脑屏障，有助于维持大脑的内稳态，并通过限制免疫细胞浸润中枢神经系统来预防神经炎症。然而，慢性脑灌注不足是否会导致 ChP 结构损伤和血脑屏障功能障碍仍研究不足。

方法

采用成年雄性 C57BL/6J 小鼠双侧颈总动脉狭窄（BCAS）模型诱导脑灌注不足，这是血管性认知障碍和痴呆（VCID）的一个模型。评估了 BCAS 介导的 TJ 蛋白、顶端分泌 Na-K-Cl 共转运蛋白同工型 1（NKCC1）蛋白和调节丝氨酸-苏氨酸激酶 SPAK 的血脑屏障 TJ 变化，以及骨髓源性免疫细胞向脑内的浸润情况。

结果

BCAS 触发 TJ 蛋白（闭合蛋白 1、闭合蛋白 5）的动态变化，同时刺激 ChP 上皮细胞中的 SPAK-NKCC1 复合物和 NF-κB。这些变化影响了血脑屏障的完整性，这可以从 ChP 中巨噬细胞/小胶质细胞、中性粒细胞和 T 细胞的浸润得到证明。重要的是，在 BCAS 小鼠中用其强效抑制剂 ZT1a 抑制 SPAK，可减轻脑免疫细胞浸润并改善认知神经功能。

结论

BCAS 导致慢性 ChP 血脑屏障损伤和免疫细胞浸润。我们的研究揭示了 SPAK-NKCC1 复合物作为神经炎症的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/916f/11385148/9d73149c5784/12974_2024_3209_Fig10_HTML.jpg
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