Mast cell activation mediates blood-brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.
Mast cell activation mediates blood-brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.
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肥大细胞激活通过组胺依赖途径介导败血症小鼠血脑屏障损伤和认知功能障碍。
DOI：
10.3389/fimmu.2023.1090288
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发表时间：
2023
影响因子：
7.3
通讯作者：
Zhang, Jiqin
中科院分区：
文献类型：
--
作者：
Yue, Jianhe;Tan, Ying;Huan, Renzheng;Guo, Jin;Yang, Sha;Deng, Mei;Xiong, Yunbiao;Han, Guoqiang;Liu, Lin;Liu, Jian;Cheng, Yuan;Zha, Yan;Zhang, Jiqin
脓毒症相关脑病（SAE）是一种由感染引起的全身炎症反应引起的弥漫性脑功能障碍；然而，其病理生理学仍不清楚。脓毒症引起的神经炎症和血脑屏障（BBB）破坏是 SAE 脑功能障碍的关键因素。肥大细胞 (MC) 激活在多种神经炎症模型中发挥着重要作用；然而，其在 SAE 中的作用尚未得到全面研究。我们首先通过盲肠结扎穿刺（CLP）手术建立SAE模型并检查MCs的激活情况。使用免疫组织化学染色和甲苯胺蓝染色检查 MC 的激活。我们给予色甘酸（10mg/ml），一种MC稳定剂，来拯救脓毒症小鼠。使用生化测定测量脑细胞因子水平。通过测量关键紧密连接 (TJ) 蛋白的水平来评估 BBB 破坏。通过Y迷宫和旷场试验分析小鼠的认知功能。使用与 MC 共培养的脑微血管内皮细胞 (BMVEC) 的 Transwell 培养物来评估 BMVEC 和 MC 的相互作用。结果显示，CLP 诱导的 SAE 小鼠海马中的 MC 过度激活。色甘酸脑室内 (i.c.v) 注射可显着抑制脓毒症小鼠的 MC 活化和神经炎症反应，改善 BBB 损伤，提高存活率并减轻认知功能障碍。在体外实验中，我们发现 MC 激活增加了 BMVEC 对脂多糖 (LPS) 攻击的敏感性。此外，我们发现组胺/组胺1受体（H1R）介导MC和BMVEC之间的相互作用，并通过调节TLR2/4-MAPK信号通路放大LPS诱导的BMVEC炎症反应。 MCs 激活可能通过组胺依赖性途径介导脓毒症小鼠的 BBB 损伤和认知功能障碍。
Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction resulting from a systemic inflammatory response to infection; however, its pathophysiology remains unclear. Sepsis-induced neuroinflammation and blood–brain barrier (BBB) disruption are crucial factors in brain function disturbance in SAE. Mast cells (MCs) activation plays an important role in several neuroinflammation models; however, its role in SAE has not been comprehensively investigated. We first established a SAE model by cecal ligation puncture (CLP) surgery and checked the activation of MCs. MCs activation was checked using immumohistochemical staining and Toluidine Blue staining. We administrated cromolyn (10mg/ml), a MC stabilizer, to rescue the septic mice. Brain cytokines levels were measured using biochemical assays. BBB disruption was assessed by measuring levels of key tight-junction (TJ) proteins. Cognitive function of mice was analyzed by Y maze and open field test. Transwell cultures of brain microvascular endothelial cells (BMVECs) co-cultured with MCs were used to assess the interaction of BMVECs and MCs. Results showed that MCs were overactivated in the hippocampus of CLP-induced SAE mice. Cromolyn intracerebroventricular (i.c.v) injection substantially inhibited the MCs activation and neuroinflammation responses, ameliorated BBB impairment, improved the survival rate and alleviated cognitive dysfunction in septic mice. In vitro experiments, we revealed that MCs activation increased the sensitivity of BMVECs against to lipopolysaccharide (LPS) challenge. Furthermore, we found that the histamine/histamine 1 receptor (H1R) mediated the interaction between MCs and BMVECs, and amplifies the LPS-induced inflammatory responses in BMVECs by modulating the TLR2/4-MAPK signaling pathway. MCs activation could mediate BBB impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.
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影响因子：
4.3
作者：
Carthy E;Ellender T
通讯作者：
Ellender T
影响因子：
7.3
作者：
Krystel-Whittemore M;Dileepan KN;Wood JG
通讯作者：
Wood JG
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre
组胺诱导组胺受体表达上调并增加小胶质细胞炎症介质的释放
影响因子：
5.1
作者：
Dong, Hongquan;Zhang, Wei;Zhang, Shu
通讯作者：
Zhang, Shu
影响因子：
3.4
作者：
Kilinc, Erkan;Torun, Ibrahim Ethem;Tore, Fatma
通讯作者：
Tore, Fatma