PMID- 37978532 OWN - NLM STAT- MEDLINE DCOM- 20231120 LR - 20231121 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 20 IP - 1 DP - 2023 Nov 17 TI - Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice. PG - 270 LID - 10.1186/s12974-023-02939-y [doi] LID - 270 AB - 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-alpha-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. CI - (c) 2023. The Author(s). FAU - Chen, Huaijun AU - Chen H AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Xu, Chaoran AU - Xu C AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Zeng, Hanhai AU - Zeng H AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Zhang, Zhihua AU - Zhang Z AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Wang, Ning AU - Wang N AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Guo, Yinghan AU - Guo Y AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Zheng, Yonghe AU - Zheng Y AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Xia, Siqi AU - Xia S AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Zhou, Hang AU - Zhou H AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Yu, Xiaobo AU - Yu X AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Fu, Xiongjie AU - Fu X AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Tang, Tianchi AU - Tang T AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Wu, Xinyan AU - Wu X AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Chen, Zihang AU - Chen Z AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Peng, Yucong AU - Peng Y AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Cai, Jing AU - Cai J AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Li, Jianru AU - Li J AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Yan, Feng AU - Yan F AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. FAU - Gu, Chi AU - Gu C AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. guchiw@zju.edu.cn. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. guchiw@zju.edu.cn. FAU - Chen, Gao AU - Chen G AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. d-chengao@zju.edu.cn. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. d-chengao@zju.edu.cn. FAU - Chen, Jingyin AU - Chen J AD - Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. cjyaway@zju.edu.cn. AD - Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, China. cjyaway@zju.edu.cn. LA - eng GR - 822201431/National Science Foundation of China/ GR - 82271398/National Science Foundation of China/ GR - 2021-zyy-04/Zhejiang Traditional Chinese Medicine Administration/ GR - 2020RC012/Zhejiang Provincial Health Innovative Talents Project/ GR - 2022C03133/Key Laboratory of Atmospheric Optics/ GR - WKJ-ZJ-2004/Key Program of Zhejiang/ PT - Journal Article DEP - 20231117 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 SB - IM MH - Humans MH - Mice MH - Male MH - Animals MH - Monocytes MH - *Subarachnoid Hemorrhage/complications MH - *Brain Injuries/etiology MH - Macrophages MH - *Stroke MH - Mice, Inbred C57BL PMC - PMC10657171 OTO - NOTNLM OT - Immune response OT - Inflammatory response OT - Ly6C high monocyte OT - Subarachnoid hemorrhage COIS- The authors declare that they have no competing interests. EDAT- 2023/11/18 11:42 MHDA- 2023/11/20 06:54 PMCR- 2023/11/17 CRDT- 2023/11/18 02:59 PHST- 2023/07/30 00:00 [received] PHST- 2023/10/27 00:00 [accepted] PHST- 2023/11/20 06:54 [medline] PHST- 2023/11/18 11:42 [pubmed] PHST- 2023/11/18 02:59 [entrez] PHST- 2023/11/17 00:00 [pmc-release] AID - 10.1186/s12974-023-02939-y [pii] AID - 2939 [pii] AID - 10.1186/s12974-023-02939-y [doi] PST - epublish SO - J Neuroinflammation. 2023 Nov 17;20(1):270. doi: 10.1186/s12974-023-02939-y.