机构：[1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University,China International Neuroscience Institute (China-INI), No.45ChangchunStreet, Xicheng District, Beijing 10053, China神经科系统神经外科首都医科大学宣武医院中国国际神经科学研究所[2]Department of Physiology andPharmacology, Department of Neurosurgery and Anesthesiology, School ofMedicine, Loma Linda University, Risley Hall, Room 219, 11041 CampusStreet, Loma Linda, CA 92354, USA[3]Department of Neurosurgery, TheAffiliated Hospital of Southwest Medical University, Luzhou 646000, China[4]Laboratory of Neurological Diseases and Brain Functions, The AffiliatedHospital of Southwest Medical University, Luzhou 646000, Sichuan, China[5]Department of Neurosurgery, Loma Linda University Medical Center, LomaLinda, CA 92354, USA
Background 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. Methods 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. Results 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 naive and ICH mice. COG1410 was associated with upregulation of TREM2, PI3K, phosphorylated-Akt, and Bcl-2 and downregulation of TNF-alpha, IL-1 beta, and Bax after ICH. The neuroprotective effects of COG1410 were abolished by both TREM2 siRNA and PI3K inhibitor LY294002. Conclusions 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.
基金：
National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS091042, NS082184]; China Postdoctoral Science FoundationChina Postdoctoral Science Foundation [2019 M660713]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81801176, 81971132, 8167120]
第一作者机构：[1]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University,China International Neuroscience Institute (China-INI), No.45ChangchunStreet, Xicheng District, Beijing 10053, China[2]Department of Physiology andPharmacology, Department of Neurosurgery and Anesthesiology, School ofMedicine, Loma Linda University, Risley Hall, Room 219, 11041 CampusStreet, Loma Linda, CA 92354, USA
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推荐引用方式(GB/T 7714)：
Shengpan Chen,Jianhua Peng,Prativa Sherchan,et al.TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice[J].JOURNAL OF NEUROINFLAMMATION.2020,17(1):doi:10.1186/s12974-020-01853-x.
APA：
Shengpan Chen,Jianhua Peng,Prativa Sherchan,Yongjie Ma,Sishi Xiang...&Hongqi Zhang.(2020).TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice.JOURNAL OF NEUROINFLAMMATION,17,(1)
MLA：
Shengpan Chen,et al."TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice".JOURNAL OF NEUROINFLAMMATION 17..1(2020)
医学