TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice
Abstract 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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01853-x |
| _version_ | 1818311715074342912 |
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| author | Shengpan Chen Jianhua Peng Prativa Sherchan Yongjie Ma Sishi Xiang Feng Yan Hao Zhao Yong Jiang Ning Wang John H. Zhang Hongqi Zhang |
| author_facet | Shengpan Chen Jianhua Peng Prativa Sherchan Yongjie Ma Sishi Xiang Feng Yan Hao Zhao Yong Jiang Ning Wang John H. Zhang Hongqi Zhang |
| author_sort | Shengpan Chen |
| collection | DOAJ |
| description | Abstract 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 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. 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. |
| first_indexed | 2024-12-13T08:06:21Z |
| format | Article |
| id | doaj.art-e402c7945f4d41b99c235df0729e377a |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-13T08:06:21Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e402c7945f4d41b99c235df0729e377a2022-12-21T23:54:19ZengBMCJournal of Neuroinflammation1742-20942020-05-0117111610.1186/s12974-020-01853-xTREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in miceShengpan Chen0Jianhua Peng1Prativa Sherchan2Yongjie Ma3Sishi Xiang4Feng Yan5Hao Zhao6Yong Jiang7Ning Wang8John H. Zhang9Hongqi Zhang10Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Physiology and Pharmacology, Department of Neurosurgery and Anesthesiology, School of Medicine, Loma Linda UniversityDepartment of Physiology and Pharmacology, Department of Neurosurgery and Anesthesiology, School of Medicine, Loma Linda UniversityDepartment of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Neurosurgery, The Affiliated Hospital of Southwest Medical UniversityDepartment of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Department of Physiology and Pharmacology, Department of Neurosurgery and Anesthesiology, School of Medicine, Loma Linda UniversityDepartment of Neurosurgery, Xuanwu Hospital, Capital Medical University, China International Neuroscience Institute (China-INI)Abstract 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 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. 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.http://link.springer.com/article/10.1186/s12974-020-01853-xIntracerebral hemorrhageTREM2ApoENeuroinflammationApoptosis |
| spellingShingle | Shengpan Chen Jianhua Peng Prativa Sherchan Yongjie Ma Sishi Xiang Feng Yan Hao Zhao Yong Jiang Ning Wang John H. Zhang Hongqi Zhang TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice Journal of Neuroinflammation Intracerebral hemorrhage TREM2 ApoE Neuroinflammation Apoptosis |
| title | TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice |
| title_full | TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice |
| title_fullStr | TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice |
| title_full_unstemmed | TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice |
| title_short | TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice |
| title_sort | trem2 activation attenuates neuroinflammation and neuronal apoptosis via pi3k akt pathway after intracerebral hemorrhage in mice |
| topic | Intracerebral hemorrhage TREM2 ApoE Neuroinflammation Apoptosis |
| url | http://link.springer.com/article/10.1186/s12974-020-01853-x |
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