TIMP1通过抑制星形胶质细胞β1-整合素的泛素化来防止蛛网膜下腔出血后血脑屏障的破坏。

IF 2.6 1区医学

Journal of Investigative Medicine Pub Date : 2024-03-14 DOI:10.1136/svn-2023-002956

Tianchi Tang, Huaijun Chen, Libin Hu, Jingya Ye, Chaohui Jing, Chaoran Xu, Xinyan Wu, Yike Chen, Zihang Chen, Hang Zhou, Linfeng Fan, Xiongjie Fu, Cong Qian, Jingsen Chen, Zhongju Tan, Jing Liu, Hanhai Zeng, Gao Chen, Fuyi Liu

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引用次数: 0

摘要

背景：星形胶质细胞调节血脑屏障（BBB）的完整性，而蛛网膜下腔出血（SAH）会导致星形胶质细胞失调和BBB破坏。在此，我们探讨了基质金属蛋白酶组织抑制剂-1（TIMP1）在 SAH 期间参与星形胶质细胞介导的血脑屏障保护及其潜在机制：方法：用 C57BL/6J 小鼠建立 SAH 模型。方法：用 C57BL/6J 小鼠建立 SAH 模型，通过腹腔注射重组小鼠 TIMP1 蛋白（rm-TIMP1；250 µg/kg）分析 TIMP1 对 SAH 结局的影响。通过体内转导携带 TIMP1 过表达质粒或 β1-integrin RNAi 的星形胶质细胞靶向腺相关病毒，观察了 TIMP1 及其效应物 β1-integrin 对星形胶质细胞的作用。在用红细胞（RBCs）刺激原代培养的星形胶质细胞中探讨了TIMP1和β1-整合素相互作用的分子机制：结果：TIMP1 在 SAH 后上调。给雄性和雌性小鼠注射 rm-TIMP1 可减轻 SAH 引起的早期脑损伤（EBI）。TIMP1 主要在星形胶质细胞中表达；其在星形胶质细胞中的过表达导致β1-整合素在星形胶质细胞中的表达增加，同时星形胶质细胞内足附着于内皮，内皮紧密连接随之恢复。敲除星形胶质细胞中的β1-整合素可逆转所有这些效应。分子分析表明，TIMP1 的过表达减少了 RBC 诱导的 β1-integrin 泛素化；这种效果部分是通过抑制 β1-integrin 与 E3 泛素连接酶 Trim21 之间的相互作用实现的：结论：TIMP1能抑制星形胶质细胞中β1-整合素与Trim21之间的相互作用，从而挽救星形胶质细胞β1-整合素的泛素化。它随后恢复了星形胶质细胞内膜与内皮之间的相互作用以及 BBB 的完整性，最终减轻了 SAH 引起的 EBI。

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TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin.

Background: Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms.

Methods: C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector β1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or β1-integrin RNAi. The molecular mechanisms underlying TIMP1 and β1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs).

Results: TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased β1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of β1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of β1-integrin; this effect was partially achieved by inhibiting the interaction between β1-integrin and the E3 ubiquitin ligase Trim21.

Conclusion: TIMP1 inhibits the interaction between β1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic β1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI.

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来源期刊

Journal of Investigative Medicine MEDICINE, GENERAL & INTERNALMEDICINE, RESE-MEDICINE, RESEARCH & EXPERIMENTAL

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发文量

111

期刊介绍： Journal of Investigative Medicine (JIM) is the official publication of the American Federation for Medical Research. The journal is peer-reviewed and publishes high-quality original articles and reviews in the areas of basic, clinical, and translational medical research. JIM publishes on all topics and specialty areas that are critical to the conduct of the entire spectrum of biomedical research: from the translation of clinical observations at the bedside, to basic and animal research to clinical research and the implementation of innovative medical care.