TREM2 通过上调 IRAK3 表达来调节神经炎症，并在大鼠实验性蛛网膜下腔出血后发挥神经保护作用。
TREM2 modulates neuroinflammation with elevated IRAK3 expression and plays a neuroprotective role after experimental SAH in rats.
机构信息
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China; Department of Neurocritical Intensive Care Unit, The Affiliated Jiangyin Hospital, School of Medicine, Southeast University, Jiangyin City 214400, Jiangsu Province, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu Province, China.
出版信息
Neurobiol Dis. 2022 Sep;171:105809. doi: 10.1016/j.nbd.2022.105809. Epub 2022 Jul 1.
BACKGROUND
The modulation of neuroinflammation is a new direction that may alleviate the early brain injury after subarachnoid hemorrhage (SAH). Brain resident microglia/macrophages (Mi/MΦ) are the key drivers of neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to play a neuroprotective role by activating phagocytosis and suspending inflammatory response in experimental ischemic stroke and intracerebral hemorrhage. This study was designed to investigate the role of TREM2 on neuroinflammation and neuroprotective effects in a rat SAH model.
METHODS
Adult male Sprague-Dawley rats were induced SAH through endovascular perforation. Lentivirus vectors were administered by i.c.v. to induce TREM2 overexpression or knockdown 7 days before SAH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence, enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling and Nissl staining were performed to explore the neuroprotective role of TREM2 after SAH.
RESULTS
The expression of TREM2 elevated in a rat SAH model with a peak at 48 h after SAH and mainly expressed in Mi/MΦ in brain. TREM2 overexpression improved short- and long-term neurological deficits induced by SAH in rats, while TREM2 knockdown worsened neurological dysfunction. The rats with TREM2 overexpressed presented less neuronal apoptosis and more neuronal survival at 48 h after SAH, while the rats with TREM2 knockdown presented on the contrary. TREM2 overexpression manifested activated phagocytosis and suppressed inflammatory response, with the increase of CD206/CD11b cells and IL-10 expression as well as the decrease of the infiltration of MPO cells and the expression of TNF-α, IL-1β. While TREM2 knockdown abolished these effects. The protein level of IRAK3, a negative regulatory factor of inflammation, was significantly elevated after TREM2 overexpression and declined after TREM2 knockdown.
CONCLUSIONS
Our research suggested TREM2 played a neuroprotective role and improved the short- and long-term neurological deficits by modulating neuroinflammation after SAH. The modulation on neuroinflammation of TREM2 after SAH was related with the elevated protein level of IRAK3.
背景
神经炎症的调节可能是减轻蛛网膜下腔出血（SAH）后早期脑损伤的一个新方向。脑固有小胶质细胞/巨噬细胞（Mi/MΦ）是神经炎症的关键驱动因素。触发受体表达在髓样细胞 2（TREM2）已被报道通过激活吞噬作用和悬浮在实验性缺血性中风和脑出血中的炎症反应发挥神经保护作用。本研究旨在探讨 TREM2 在大鼠 SAH 模型中的神经炎症和神经保护作用。
方法
成年雄性 Sprague-Dawley 大鼠通过血管内穿孔诱导 SAH。通过 i.c.v. 给予慢病毒载体诱导 TREM2 过表达或敲低，在 SAH 诱导前 7 天。进行短期和长期神经行为测试、western blot、免疫荧光、酶联免疫吸附试验、末端脱氧核苷酸转移酶 dUTP 缺口末端标记和尼氏染色，以探讨 TREM2 在 SAH 后的神经保护作用。
结果
TREM2 在大鼠 SAH 模型中的表达在 SAH 后 48 小时达到峰值，主要在大脑中的 Mi/MΦ 中表达。TREM2 过表达改善了大鼠 SAH 引起的短期和长期神经功能缺损，而 TREM2 敲低则加重了神经功能障碍。TREM2 过表达的大鼠在 SAH 后 48 小时表现出较少的神经元凋亡和更多的神经元存活，而 TREM2 敲低的大鼠则相反。TREM2 过表达表现出激活的吞噬作用和抑制炎症反应，伴随着 CD206/CD11b 细胞和 IL-10 表达的增加以及 MPO 细胞浸润和 TNF-α、IL-1β表达的减少。而 TREM2 敲低则消除了这些效应。TREM2 过表达后 IRAK3 的蛋白水平（炎症的负调节因子）显著升高，TREM2 敲低后 IRAK3 的蛋白水平下降。
结论
我们的研究表明，TREM2 通过调节 SAH 后的神经炎症，发挥神经保护作用，改善短期和长期神经功能缺损。SAH 后 TREM2 对神经炎症的调节与 IRAK3 蛋白水平的升高有关。
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