神经炎症是蛛网膜下腔出血（SAH）引起脑损伤的重要机制。 C-C 趋化因子受体 1 型 (CCR1) 介导的炎症参与许多中枢神经系统疾病的病理学。在此，我们研究了抑制CCR1是否可以减轻实验性SAH后的神经炎症，并旨在阐明其潜在保护作用的机制。为了分析SAH转录组数据，使用了R studio，并利用血管内穿孔建立了SAH小鼠模型。在此模型中，SAH 诱导后 1 小时施用选择性 CCR1 拮抗剂 Met-RANTES (Met-R) 和 CCR1 激动剂重组 CCL5 (rCCL5)。为了研究 CCR1 可能的下游机制，在 SAH 诱导后 1 小时施用 JAK2 抑制剂 AG490 和 JAK2 激活剂香豆霉素 A1 (C-A1)。此外，还进行了SAH后评估，包括SAH分级、神经功能测试、蛋白质印迹、末端脱氧核苷酸转移酶dUTP缺口末端标记测定以及Fluoro-Jade B和荧光免疫组化染色。通过ELISA检测脑脊液(CSF)样本。SAH后CCL5和CCR1表达水平显着增加。 Met-R 显着改善小鼠的神经功能缺损，减少同侧大脑皮层神经元的凋亡和变性，减少浸润性中性粒细胞，并促进 SAH 诱导后的小胶质细胞活化。此外，Met-R 抑制 p-JAK2、p-STAT3、白介素-1β 和肿瘤坏死因子-α 的表达。然而，C-A1 治疗消除了 Met-R 的保护作用。此外，注射rCCL5会加重SAH小鼠的神经功能障碍，并增加p-JAK2、p-STAT3、白细胞介素-1β和肿瘤坏死因子-α的表达，所有这些都被AG490的给药所逆转。最后，SAH 患者脑脊液中 CCL5 和 CCR1 的水平升高，高水平的 CCL5 和 CCR1 与不良预后相关。目前的结果表明，抑制 CCR1 可通过 JAK2/STAT3 信号通路减轻 SAH 后的神经炎症。这可能为 SAH 的治疗提供新的靶点。版权所有 © 2023 Elsevier B.V. 保留所有权利。

Neuroinflammation is an important mechanism underlying brain injury caused by subarachnoid hemorrhage (SAH). C-C chemokine receptor type 1 (CCR1)-mediated inflammation is involved in the pathology of many central nervous system diseases. Herein, we investigated whether inhibition of CCR1 alleviated neuroinflammation after experimental SAH and aimed to elucidate the mechanisms of its potential protective effects.To analyze SAH transcriptome data R studio was used, and a mouse model of SAH was established using endovascular perforations. In this model, the selective CCR1 antagonist Met-RANTES (Met-R) and the CCR1 agonist recombinant CCL5 (rCCL5) were administered 1 h after SAH induction. To investigate the possible downstream mechanisms of CCR1, the JAK2 inhibitor AG490 and the JAK2 activator coumermycin A1 (C-A1) were administered 1 h after SAH induction. Furthermore, post-SAH evaluation, including SAH grading, neurological function tests, Western blot, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Fluoro-Jade B and fluorescent immunohistochemical staining were performed. Cerebrospinal fluid (CSF) samples were detected by ELISA.CCL5 and CCR1 expression levels increased significantly following SAH. Met-R significantly improved neurological deficits in mice, decreased apoptosis and degeneration of ipsilateral cerebral cortex neurons, reduced infiltrating neutrophils, and promoted microglial activation after SAH induction. Furthermore, Met-R inhibited the expression of p-JAK2, p-STAT3, interleukin-1β, and tumor necrosis factor-α. However, the protective effects of Met-R were abolished by C-A1 treatment. Furthermore, rCCL5 injection aggravated neurological dysfunction and increased the expression of p-JAK2, p-STAT3, interleukin-1β, and tumor necrosis factor-α in SAH mice, all of which were reversed by the administration of AG490. Finally, the levels of CCL5 and CCR1 were elevate in the CSF of SAH patient and high level of CCL5 and CCR1 levels were associated with poor outcome.The present results suggested that inhibition of CCR1 attenuates neuroinflammation after SAH via the JAK2/STAT3 signaling pathway, which may provide a new target for the treatment of SAH.Copyright © 2023 Elsevier B.V. All rights reserved.