Mast cell activation mediates blood-brain barrier impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway

作者全名："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"

作者地址："[Yue, Jianhe; Huan, Renzheng; Cheng, Yuan] Chongqing Med Univ, Dept Neurosurg, Affiliated Hosp 2, Chongqing, Peoples R China; [Tan, Ying; Guo, Jin; Yang, Sha; Deng, Mei; Xiong, Yunbiao; Han, Guoqiang; Liu, Lin; Liu, Jian] Guizhou Prov Peoples Hosp, Dept Neurosurg, Guiyang, Peoples R China; [Zha, Yan] Guizhou Prov Peoples Hosp, Dept Nephrol, Guiyang, Peoples R China; [Zhang, Jiqin] Guizhou Prov Peoples Hosp, Dept Anesthesiol, Guiyang, Peoples R China"

通信作者："Cheng, Y (通讯作者)，Chongqing Med Univ, Dept Neurosurg, Affiliated Hosp 2, Chongqing, Peoples R China.; Zha, Y (通讯作者)，Guizhou Prov Peoples Hosp, Dept Nephrol, Guiyang, Peoples R China.; Zhang, JQ (通讯作者)，Guizhou Prov Peoples Hosp, Dept Anesthesiol, Guiyang, Peoples R China."

来源：FRONTIERS IN IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000932888000001

JCR分区：Q1

影响因子：7.3

年份：2023

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：mast cell; sepsis-associated encephalopathy; neuroinflammation; blood-brain barrier; histamine

摘要："IntroductionSepsis-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. MethodsWe 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. ResultsResults 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. ConclusionsMCs activation could mediate BBB impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway."

基金机构："National Natural Science Foundation of China [81960454, 81960344, 82260533]; Guizhou Provincial Science and Technology Projects [[2020]1Y322]; Guizhou Provincial People's Hospital Doctor Foundation [[2018]06, [2018]03]; Guizhou Provincial People's Hospital National Science Foundation [GPPH-NSFC-2019-09, GPPH-NSFC-2019-18, GPPH-NSFC-D-2019-17]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81960454, 81960344 and 82260533), Guizhou Provincial Science and Technology Projects ([2020]1Y322), Guizhou Provincial People's Hospital Doctor Foundation ([2018]06 and [2018]03) and Guizhou Provincial People's Hospital National Science Foundation (GPPH-NSFC-2019-09, GPPH-NSFC-2019-18, GPPH-NSFC-D-2019-17)."