TREM (Triggering Receptor Expressed on Myeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC (Protein Kinase C) δ/CARD9 (Caspase Recruitment Domain Family Member 9) Signaling Pathway After Intracerebral Hemorrhage in Mice.
TREM (Triggering Receptor Expressed on Myeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC (Protein Kinase C) δ/CARD9 (Caspase Recruitment Domain Family Member 9) Signaling Pathway After Intracerebral Hemorrhage in Mice.
复制标题
TREM（髓系细胞上表达的触发受体）-1抑制通过PKC（蛋白激酶C） δ/CARD9 （Caspase募集结构域家族成员9）信号通路减轻小鼠脑出血后的神经炎症
DOI：
10.1161/strokeaha.120.032736
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发表时间：
2021-06
期刊：
影响因子：
8.3
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Lu Q;Liu R;Sherchan P;Ren R;He W;Fang Y;Huang Y;Shi H;Tang L;Yang S;Zhang JH;Tang J
脑出血（ICH）是脑卒中的一种破坏性亚型，具有高死亡率和致残率。炎症反应促进ICH后继发性脑损伤。髓样细胞上表达的触发受体1（TREM-1）是炎症的关键调节因子。本研究的目的是评估TREM-1在小鼠脑出血后神经炎症反应中的作用。本研究中使用了CD 1小鼠（n=275）。通过自体血液注射使小鼠经受ICH。脑室内施用TREM-1敲除CRISPR以评估TREM-1在ICH后的作用。选择性TREM-1抑制剂LP 17在ICH后2小时鼻内给药。为了阐明TREM-1信号传导途径，将CARD 9活化CRISPR与LP 17一起施用，并将TREM-1活化抗小鼠TREM-1抗体（mAb）与Rottlerin（一种特异性PKC δ抑制剂）一起施用。最后，为了评估HMGB 1在TREM-1介导的小胶质细胞活化中的作用，将HMBG 1的抑制剂甘草甜素与TREM-1活化mAb一起施用。进行神经行为学测试、脑含水量测定、免疫印迹、免疫荧光染色和免疫共沉淀。TREM-1基因敲除可减少ICH诱导的神经行为缺陷和神经炎症反应。脑出血后HMGB 1、TREM-1、PKC δ和CARD 9的表达时间性增加。TREM-1在小胶质细胞上表达。鼻内给予LP 17可显著减轻脑水肿，并改善ICH后24 h和72 h的神经行为结局。LP 17促进M2小胶质细胞极化并减少ICH后的促炎细胞因子，这被CARD 9激活CRISPR逆转。TREM-1 mAb增加了ICH后的神经行为缺陷、促炎细胞因子和减少的M2小胶质细胞，这被Rottlerin逆转。HMBG 1与TREM-1的相互作用在ICH后增加，甘草酸减少神经炎症并促进M2小胶质细胞，这被TREM-1 mAb逆转。本研究表明，TREM-1通过调节脑出血后小胶质细胞的极化来增强神经炎症，这种调节部分通过PKC δ/CARD 9信号通路介导，并增加TREM-1的HMGB 1活化。
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability. Inflammatory response promotes secondary brain injury after ICH. Triggering receptor expressed on myeloid cells 1 (TREM-1) is a key regulator of inflammation. The aim of this study was to evaluate the role of TREM-1 in neuroinflammatory response after ICH in mice. CD1 mice (n=275) were used in this study. Mice were subjected to ICH by autologous blood injection. TREM-1 knockout CRISPR was administered intracerebroventricularly to evaluate the role of TREM-1 after ICH. A selective TREM-1 inhibitor, LP17 was administered intranasally 2h after ICH. To elucidate TREM-1 signaling pathway, CARD9 activation CRISPR was administered with LP17 and TREM-1 activating anti-mouse TREM-1 antibody (mAb) was administered with Rottlerin, a specific PKC δ inhibitor. Lastly, to evaluate the role of HMGB1 in TREM-1 mediated microglia activation, Glycyrrhizin, an inhibitor of HMBG1 was administered with TREM-1 activating mAb. Neurobehavioral test, brain water content, western blot, immunofluorescence staining and co-immunoprecipitation was performed. TREM-1 knockout reduced ICH-induced neurobehavioral deficits and neuroinflammatory response. The temporal expression of HMGB1, TREM-1, PKC δ and CARD9 increased after ICH. TREM-1 was expressed on microglia. Intranasal administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24h and 72h after ICH. LP17 promoted M2 microglia polarization and reduced proinflammatory cytokines after ICH, which was reversed with CARD9 activation CRISPR. TREM-1 mAb increased neurobehavior deficits, proinflammatory cytokines and reduced M2 microglia after ICH, which was reversed with Rottlerin. HMBG1 interaction with TREM-1 increased after ICH, and Glycyrrhizin reduced neuroinflammation and promoted M2 microglia which was reversed with TREM-1 mAb. This study demonstrated that TREM-1 enhanced neuroinflammation by modulating microglia polarization after ICH, and this regulation was partly mediated via PKC δ/CARD9 signaling pathway and increased HMGB1 activation of TREM-1.