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Activated Microglia Exosomes Mediated miR-383-3p Promotes Neuronal Necroptosis Through Inhibiting ATF4 Expression in Intracerebral Hemorrhage

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Abstract

Intracerebral hemorrhage (ICH) is the second largest type of stroke, with high mortality and morbidity, and most patients have severe sequelae. Brain injury induced by ICH includes primary damage and secondary damage, and the secondary brain injury is the main reason of neurological impairment. The hallmark of secondary brain injury is cell death. Necroptosis is a type of the cell death and plays vital roles in various neurological diseases, but the roles of necroptosis in ICH are still not fully known. Microglia cell is the type of immune cell, plays protective roles in nerve damage and modulates the activity of neurons through secreting exosomes. Exosome-contained miRNAs are also involved in the regulating neuronal activity. However, the roles and the mechanisms of microglia-secreted exosomes miRNAs in ICH neurons necroptosis need to further explore. In this study, ICH model was construct in rats and cells. Injury of cells in brain was detected by PI staining. Necroptosis in rats and cells was detected by western blot and flow cytometry. The expression of miR-383-3p was detected by RT-qPCR. The roles of activated microglia-secreted exosomes and exosome-contained miR-383-3p were detected through co-culturing medium or exosomes with neurons. The target gene of miR-383-3p was determined by luciferase assay and the expression of target gene was detected by western blot. Rescue experiments were used to confirm the mechanism of miR-383-3p in neurons necroptosis. The miR-383-3p role was verified in vivo through injecting miR-383-3p mimic into ICH rats. Here, we found that the necroptosis of neurons was increased in ICH rats through detecting the expression of RIP1 and RIP3 and PI staining. Microglia that activated by ICH promote neurons necroptosis through secreting exosomes and transferring miR-383-3p into neurons. In mechanism, miR-383-3p negatively regulated the expression of ATF4 and then promoted the necroptosis of neurons. Overall, our results provide a novel molecular basis to neurons necroptosis in ICH and may provide a new strategy to retard the secondary brain injury of ICH.

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Funding

Jiangsu Provincial Commission of Health and Family Planning (H2018064) by Prof. Hengzhu Zhang. Jiangsu Province 333 Project (BRA2019026) by Prof. Hengzhu Zhang. Six One Project in Jiangsu Province (CN) (LGY2017026) by Prof. Hengzhu Zhang.

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  1. Min Wei, Chen Li and Zhengcun Yan have contributed equally to this article.

Authors and Affiliations

  1. Department of Neurosurgery, Clinical Medical College, Yangzhou University, No. 98 of Nantong West Road, Yangzhou, 225001, Jiangsu Province, China

    Min Wei, Chen Li, Zhengcun Yan, Zhengwei Hu, Lun Dong, Jun Zhang, Xingdong Wang, Yuping Li & Hengzhu Zhang

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Wei, M., Li, C., Yan, Z. et al. Activated Microglia Exosomes Mediated miR-383-3p Promotes Neuronal Necroptosis Through Inhibiting ATF4 Expression in Intracerebral Hemorrhage. Neurochem Res 46, 1337–1349 (2021). https://doi.org/10.1007/s11064-021-03268-3

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