Neuroinflammation is an important host defense response to secondary brain injury after intracerebral hemorrhage (ICH). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects by attenuating neuroinflammation in experimental ischemic stroke. Recent studies suggest that apolipoprotein E (apoE) is a novel, high-affinity ligand of TREM2. This study aimed to investigate the effects of TREM2 activation on neuroinflammation and neuronal apoptosis in a mouse model of ICH. Adult male CD1 mice (n = 216) were subjected to intrastriatal injection of bacterial collagenase. The TREM2 ligand, apoE-mimetic peptide COG1410 was administered intranasally at 1 h after ICH induction. To elucidate the underlying mechanism, TREM2 small interfering RNA (siRNA) and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were administered intracerebroventricularly prior to COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, western blotting, and Fluoro-Jade C- and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Endogenous TREM2 expression was increased and peaked at 24 h after ICH. TREM2 was expressed on microglia, astrocytes, and neurons. COG1410 improved both short-term and long-term neurological functions, reduced brain edema, inhibited microglia/macrophage activation and neutrophil infiltration, and suppressed neuronal apoptotic cell death in perihematomal areas after ICH. Knockdown of endogenous TREM2 by TREM2 siRNA aggravated neurological deficits and decreased the expression of TREM2 in naïve and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-α, IL-1β, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002. Our finding demonstrated that TREM2 activation improved neurological functions and attenuated neuroinflammation and neuronal apoptosis after ICH, which was, at least in part, mediated by activation of PI3K/Akt signaling pathway. Therefore, activation of TREM2 may be a potential therapeutic strategy for the management of ICH patients.

中文翻译：

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小鼠脑出血后，TREM2激活可通过PI3K / Akt途径减弱神经炎症和神经元凋亡。

神经炎症是脑出血（ICH）后继发性脑损伤的重要宿主防御反应。髓样细胞2（TREM2）上表达的触发受体通过减弱实验性缺血性脑卒中的神经炎症而赋予强大的神经保护作用。最近的研究表明，载脂蛋白E（apoE）是TREM2的新型，高亲和力配体。这项研究旨在调查TREM2激活对ICH小鼠模型中神经炎症和神经元凋亡的影响。成年雄性CD1小鼠（n = 216）进行纹状体内注射细菌胶原酶。在ICH诱导后1小时鼻内施用TREM2配体apoE模拟肽COG1410。为了阐明基本机制，在COG1410治疗之前，需在脑室内给予TREM2小干扰RNA（siRNA）和磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002。进行了神经行为学测试，脑水含量，免疫荧光，蛋白质印迹以及Fluoro-Jade C-和末端脱氧核苷酸转移酶dUTP缺口末端标记染色。ICH后24 h，内源性TREM2表达增加并达到峰值。TREM2在小胶质细胞，星形胶质细胞和神经元上表达。COG1410改善了短期和长期的神经功能，减少了脑水肿，抑制了小胶质细胞/巨噬细胞的活化和中性粒细胞浸润，并抑制了脑出血后脑出血周围神经元的凋亡细胞死亡。TREM2 siRNA敲除内源性TREM2会加剧幼稚和ICH小鼠的神经功能缺损，并降低TREM2的表达。COG1410与ICH后TREM2，PI3K，磷酸化Akt和Bcl-2的上调以及TNF-α，IL-1β和Bax的下调有关。TREM2 siRNA和PI3K抑制剂LY294002都消除了COG1410的神经保护作用。我们的发现表明，ICH后TREM2激活改善了神经功能，减轻了神经炎症和神经元凋亡，这至少部分是由PI3K / Akt信号通路的激活介导的。因此，TREM2的激活可能是治疗ICH患者的潜在治疗策略。和ICH之后的Bax。TREM2 siRNA和PI3K抑制剂LY294002都消除了COG1410的神经保护作用。我们的发现表明，ICH后TREM2激活改善了神经功能，减轻了神经炎症和神经元凋亡，这至少部分是由PI3K / Akt信号通路的激活介导的。因此，TREM2的激活可能是治疗ICH患者的潜在治疗策略。和ICH之后的Bax。TREM2 siRNA和PI3K抑制剂LY294002都消除了COG1410的神经保护作用。我们的发现表明，ICH后TREM2激活改善了神经功能，减轻了神经炎症和神经元凋亡，这至少部分是由PI3K / Akt信号通路的激活介导的。因此，TREM2的激活可能是治疗ICH患者的潜在治疗策略。