Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice
Abstract Background Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the c...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02939-y |
| _version_ | 1797557602078425088 |
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| author | Huaijun Chen Chaoran Xu Hanhai Zeng Zhihua Zhang Ning Wang Yinghan Guo Yonghe Zheng Siqi Xia Hang Zhou Xiaobo Yu Xiongjie Fu Tianchi Tang Xinyan Wu Zihang Chen Yucong Peng Jing Cai Jianru Li Feng Yan Chi Gu Gao Chen Jingyin Chen |
| author_facet | Huaijun Chen Chaoran Xu Hanhai Zeng Zhihua Zhang Ning Wang Yinghan Guo Yonghe Zheng Siqi Xia Hang Zhou Xiaobo Yu Xiongjie Fu Tianchi Tang Xinyan Wu Zihang Chen Yucong Peng Jing Cai Jianru Li Feng Yan Chi Gu Gao Chen Jingyin Chen |
| author_sort | Huaijun Chen |
| collection | DOAJ |
| description | Abstract Background Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. Methods A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. Results The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. Conclusions Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH. |
| first_indexed | 2024-03-10T17:19:10Z |
| format | Article |
| id | doaj.art-4e90c1634dec43a8a8d3328197469c1d |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:10Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-4e90c1634dec43a8a8d3328197469c1d2023-11-20T10:24:11ZengBMCJournal of Neuroinflammation1742-20942023-11-0120111710.1186/s12974-023-02939-yLy6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in miceHuaijun Chen0Chaoran Xu1Hanhai Zeng2Zhihua Zhang3Ning Wang4Yinghan Guo5Yonghe Zheng6Siqi Xia7Hang Zhou8Xiaobo Yu9Xiongjie Fu10Tianchi Tang11Xinyan Wu12Zihang Chen13Yucong Peng14Jing Cai15Jianru Li16Feng Yan17Chi Gu18Gao Chen19Jingyin Chen20Department 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 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 Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. Methods A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. Results The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. Conclusions Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.https://doi.org/10.1186/s12974-023-02939-ySubarachnoid hemorrhageInflammatory responseImmune responseLy6C high monocyte |
| spellingShingle | Huaijun Chen Chaoran Xu Hanhai Zeng Zhihua Zhang Ning Wang Yinghan Guo Yonghe Zheng Siqi Xia Hang Zhou Xiaobo Yu Xiongjie Fu Tianchi Tang Xinyan Wu Zihang Chen Yucong Peng Jing Cai Jianru Li Feng Yan Chi Gu Gao Chen Jingyin Chen Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice Journal of Neuroinflammation Subarachnoid hemorrhage Inflammatory response Immune response Ly6C high monocyte |
| title | Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| title_full | Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| title_fullStr | Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| title_full_unstemmed | Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| title_short | Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| title_sort | ly6c high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice |
| topic | Subarachnoid hemorrhage Inflammatory response Immune response Ly6C high monocyte |
| url | https://doi.org/10.1186/s12974-023-02939-y |
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