Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke
Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke
复制标题
小胶质细胞 TREM-1 受体通过与 SYK 相互作用介导实验性缺血性卒中神经炎症损伤
DOI：
10.1038/s41419-019-1777-9
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发表时间：
2019-07-19
影响因子：
9
通讯作者：
Xu, Gelin
中科院分区：
文献类型：
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作者：
Xu, Pengfei;Zhang, Xiaohao;Xu, Gelin
神经炎症是对缺血性中风的反应，通常具有小胶质细胞激活和侧支脑损伤的特征，这些特征是由强烈的炎症作用引起的。骨髓细胞上表达的触发受体(TREM)-1是先天免疫反应的放大器，是炎症的关键调节因子。本研究发现脑缺血损伤后小胶质细胞TREM-1表达上调。合成肽LP17对TREM-1进行药理学抑制后，缺血性梗死和神经元损伤明显减轻。此外，阻断TREM-1可以增强海马细胞增殖和突触可塑性，从而导致长期功能改善。由于LP17降低了M1标记物的mRNA水平、趋化因子以及髓过氧化物酶和细胞内粘附分子-1 （ICAM-1）的蛋白水平，小胶质细胞M1极化和中性粒细胞募集明显减少。从机制上讲，在体内和体外，我们都发现TREM-1可以通过与脾酪氨酸激酶（SYK）相互作用，激活下游促炎途径CARD9/NF-κB和NLRP3/caspase-1。此外，trem -1诱导的SYK起始通过提高小胶质细胞内气皮蛋白D （GSDMD）、GSDMD n端片段（GSDMD- n）的水平，并形成GSDMD孔，促进细胞内炎症因子的释放，从而导致小胶质细胞焦亡。综上所述，小胶质TREM-1受体通过与SYK相关而导致脑卒中后神经炎症损伤。
Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-κB, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.