Macrophage-Inducible C-Type Lectin/Spleen Tyrosine Kinase Signaling Pathway Contributes to Neuroinflammation After Subarachnoid Hemorrhage in Rats.
Macrophage-Inducible C-Type Lectin/Spleen Tyrosine Kinase Signaling Pathway Contributes to Neuroinflammation After Subarachnoid Hemorrhage in Rats.
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DOI：
10.1161/strokeaha.115.010088
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发表时间：
2015-08
期刊：
影响因子：
8.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
He Y;Xu L;Li B;Guo ZN;Hu Q;Guo Z;Tang J;Chen Y;Zhang Y;Tang J;Zhang JH
Mincle(巨噬细胞诱导的C型凝集素，CLEC4E)受体参与了脑缺血和创伤性脑损伤的神经炎症反应。本研究旨在探讨Mincle及其下游Syk信号通路在蛛网膜下腔出血后早期脑损伤中的作用。雄性SD大鼠215只(280-320g)建立蛛网膜下腔出血血管内穿孔模型。于SAH后24 h检测SAH评分、神经功能评分和脑含水量。免疫印迹法检测蛛网膜下腔出血后2 4h脑组织Mincle/Syk、CARD9(半胱氨酸天冬氨酸氨基转移酶相关募集结构域(CARD)成员)、白细胞介素1β(IL 1β)和髓过氧化物酶(MPO)的表达。用双重免疫荧光染色检测表达Mincle的特定细胞类型。使用Mincle受体SAP130的内源性配体Mincle siRNA和选择性Syk磷酸化抑制剂Piceatanyl进行干预。SAH后大鼠脑含水量增加，神经功能下降。SAP130、Mincle、Syk和p-Syk的表达在SAH后12h开始升高，在SAH后24h达到高峰。在蛛网膜下腔出血后24小时，小分子siRNA可减少IL-1β，减少MPO阳性细胞的浸润，减少脑含水量，改善神经功能。Mincle受体内源性配体SAP130虽不增加脑含水量，也不影响神经功能，但可上调p-Syk和CARD9的表达，增加IL-1β和MPO的水平。SYK抑制剂匹卡他诺能减轻SAH后24小时的脑水肿。Mincle/Syk参与SAH后早期脑损伤，可能成为治疗干预的新靶点。
Mincle (macrophage-inducible C-type lectin, CLEC4E) receptor is reported involved in neuroinflammation in cerebral ischemia and traumatic brain injury. This study was designed to investigate the role of Mincle and its downstream Syk signal pathway in early brain injury after SAH in a rat model. Two hundreds and fifteen (215) male Sprague-Dawley rats (280–320g) were subjected to endovascular perforation model of SAH. SAH grade, neurological score, and brain water content were measured at 24 h after SAH. Mincle/Syk as well as CARD9 (a member of the caspase-associated recruitment domain (CARD), involved in innate immune response), interleukin-1β (IL-1β) and myeloperoxidase (MPO) expressions were analyzed by western blot at 24 h after SAH. Specific cell types that expressed Mincle were detected with double immunofluorescence staining. Mincle siRNA, the endogenous ligand of Mincle receptor SAP130, and a selective Syk phosphorylation inhibitor piceatannol were used for intervention. Brain water content increased and neurological functions decreased in rats after SAH. The expression of SAP130, Mincle, Syk and p-Syk increased at 12h and peaked at 24h after SAH. Mincle siRNA reduced IL-1β and infiltration of MPO positive cells, decreased brain water content, and improved neurological functions at 24h after SAH. The endogenous ligand of Mincle receptor SAP130 up-regulated the expression of p-Syk and CARD9, and increased the levels of IL-1β and MPO, even though it did not increase brain water content nor it deteriorated neurological function at 24h after SAH. Syk inhibitor piceatannol reduced brain edema at 24h after SAH. Mincle/Syk is involved in early brain injury after SAH, and they may serve as new targets for therapeutic intervention.