CCL5/CCR5 介导的外周炎症加剧了小鼠脑出血后的血脑屏障破坏。

CCL5/CCR5-mediated peripheral inflammation exacerbates blood‒brain barrier disruption after intracerebral hemorrhage in mice.

机构信息

Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), 29 Gaotanyan Street, Shapingba District, Chongqing, 400038, China.

Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

出版信息

J Transl Med. 2023 Mar 14;21(1):196. doi: 10.1186/s12967-023-04044-3.

BACKGROUND

Owing to metabolic disequilibrium and immune suppression, intracerebral hemorrhage (ICH) patients are prone to infections; according to a recent global analysis of stroke cases, approximately 10 million new-onset ICH patients had experienced concurrent infection. However, the intrinsic mechanisms underlying the effects of infection related peripheral inflammation after ICH remain unclear.

METHODS

Lipopolysaccharide (LPS) was intraperitoneally injected into ICH model mice to induce peripheral inflammation. Neurobehavioral deficits, blood‒brain barrier (BBB) disruption, and the expression of CCR5, JAK2, STAT3, and MMP9 were evaluated after treatment with recombinant CCL5 (rCCL5) (a CCR5 ligand), maraviroc (MVC) (an FDA-approved selective CCR5 antagonist), or JAK2 CRISPR plasmids.

RESULTS

Our study revealed that severe peripheral inflammation increased CCL5/CCR5 axis activation in multiple inflammatory cell types, including microglia, astrocytes, and monocytes, and aggravated BBB disruption and neurobehavioral dysfunction after ICH, possibly in part through the JAK2/STAT3 signaling pathway.

CONCLUSIONS

CCR5 might be a potential target for the clinical treatment of infection-induced exacerbation of BBB disruption following ICH.

背景

由于代谢失衡和免疫抑制，脑出血（ICH）患者容易发生感染；根据最近对全球中风病例的分析，约有 1000 万新发 ICH 患者发生了并发感染。然而，ICH 后感染相关外周炎症影响的内在机制尚不清楚。

方法

向 ICH 模型小鼠腹腔内注射脂多糖（LPS）以诱导外周炎症。在用重组 CCL5（rCCL5）（CCR5 配体）、马拉维若（MVC）（一种 FDA 批准的选择性 CCR5 拮抗剂）或 JAK2 CRISPR 质粒处理后，评估神经行为缺陷、血脑屏障（BBB）破坏以及 CCR5、JAK2、STAT3 和 MMP9 的表达。