Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage
Abstract Background Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods A total of 344 male...
| 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/s12974-020-01830-4 |
| _version_ | 1818508623137996800 |
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| author | Yucong Peng Jianfeng Zhuang Guangyu Ying Hanhai Zeng Hang Zhou Yang Cao Huaijun Chen Chaoran Xu Xiongjie Fu Hangzhe Xu Jianru Li Shenglong Cao Jingyin Chen Chi Gu Feng Yan Gao Chen |
| author_facet | Yucong Peng Jianfeng Zhuang Guangyu Ying Hanhai Zeng Hang Zhou Yang Cao Huaijun Chen Chaoran Xu Xiongjie Fu Hangzhe Xu Jianru Li Shenglong Cao Jingyin Chen Chi Gu Feng Yan Gao Chen |
| author_sort | Yucong Peng |
| collection | DOAJ |
| description | Abstract Background Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. Conclusion Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH. |
| first_indexed | 2024-12-10T22:34:36Z |
| format | Article |
| id | doaj.art-c0dc07953fd740abb1e2fad8df00e887 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T22:34:36Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c0dc07953fd740abb1e2fad8df00e8872022-12-22T01:30:58ZengBMCJournal of Neuroinflammation1742-20942020-05-0117112010.1186/s12974-020-01830-4Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhageYucong Peng0Jianfeng Zhuang1Guangyu Ying2Hanhai Zeng3Hang Zhou4Yang Cao5Huaijun Chen6Chaoran Xu7Xiongjie Fu8Hangzhe Xu9Jianru Li10Shenglong Cao11Jingyin Chen12Chi Gu13Feng Yan14Gao Chen15Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineDepartment of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of MedicineAbstract Background Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. Conclusion Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.http://link.springer.com/article/10.1186/s12974-020-01830-4Subarachnoid hemorrhageSTINGMicrogliaNeuroinflammation |
| spellingShingle | Yucong Peng Jianfeng Zhuang Guangyu Ying Hanhai Zeng Hang Zhou Yang Cao Huaijun Chen Chaoran Xu Xiongjie Fu Hangzhe Xu Jianru Li Shenglong Cao Jingyin Chen Chi Gu Feng Yan Gao Chen Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage Journal of Neuroinflammation Subarachnoid hemorrhage STING Microglia Neuroinflammation |
| title | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage |
| title_full | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage |
| title_fullStr | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage |
| title_full_unstemmed | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage |
| title_short | Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage |
| title_sort | stimulator of ifn genes mediates neuroinflammatory injury by suppressing ampk signal in experimental subarachnoid hemorrhage |
| topic | Subarachnoid hemorrhage STING Microglia Neuroinflammation |
| url | http://link.springer.com/article/10.1186/s12974-020-01830-4 |
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