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Ferrostatin-1 Polarizes Microglial Cells Toward M2 Phenotype to Alleviate Inflammation After Intracerebral Hemorrhage

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Abstract

Background

Intracerebral hemorrhage (ICH) is one of the most lethal stroke types and lacks effective therapeutic regimens. Recently, evidence has suggested the involvement of the ferroptosis inhibitor ferrostatin-1 (Fer-1) in the pathophysiological process of ICH. In this study, we examined the underlying mechanism.

Methods

We induced an in vitro apoptosis model in organotypic hippocampal slice (OHS) using hemoglobin (Hb) and an in vivo ICH model using collagenase. OHSs were treated with MK-801, Fer-1, glutamate, and Hb to assess the impacts of Fer-1 on neuron apoptosis, glutathione peroxidase-4 activity, reactive oxygen species production, inflammation-related factors, expression of M1 markers and M2 markers, and the phagocytic function of microglial cells in vitro. Then, ICH mice were treated with Fer-1 and ruxolitinib to evaluate the effects of Fer-1-orchestrating janus kinase 1/signal transducer and activator of transcription 6 pathway on neurological function, brain water content, hematoma volume, the anti-inflammatory factor, M1 and M2 markers, and the phagocytic function of microglial cells in vivo.

Results

Hb or glutamate facilitated glutathione peroxidase dysfunction, reactive oxygen species production, and neuronal apoptosis in OHSs, which was nullified by Fer-1. Fer-1 polarized microglial cells to the M2 phenotype, enhanced their phagocytic function, and prevented inflammation in Hb-induced OHSs. In the ICH mouse model, Fer-1 was found to improve neurological function and promote hematoma absorption. In addition, Fer-1 activated the Fer-1-orchestrating janus kinase 1/signal transducer and activator of transcription 6 pathway, which accelerated microglial M2 polarization, enhanced the phagocytic function of microglial cells, and restrained inflammation in ICH mice.

Conclusions

Overall, our findings suggest that Fer-1 may be a novel mechanism underlying microglial M2 polarization and inflammation after ICH.

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable efforts and comments regarding this article.

Funding

This study was supported by Qiqihar science and Technology Bureau (SFGG-201952).

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Authors and Affiliations

  1. Department of Neurology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar Cancer Hospital, No. 27, Taishun Street, Tiefeng District, Heilongjiang, 161000, Heilongjiang Province, People’s Republic of China

    Lijuan Huang, Yanjiao Zhang, Qingyou Chen & Li Li

  2. Department of Anesthesiology, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar Cancer Hospital, Heilongjiang, People’s Republic of China

    Liang Zhao

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  1. Lijuan Huang
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Contributions

Lijuan Huang and Yanjiao Zhang participated in the conception and design of the study. Liang Zhao and Qingyou Chen performed the analysis and interpretation of data. Li Li contributed to drafting the article. Lijuan Huang and Yanjiao Zhang revised it critically for important intellectual content. Liang Zhao is the guarantor for the article who accepts full responsibility for the work and/or the conduct of the study, had access to the data, and oversaw the decision to publish. The final manuscript was approved by all authors.

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Correspondence to Li Li.

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Ethical Approval/Human and Animal Rights

We confirm that this manuscript adheres to ethical guidelines and indicate ethical approvals (institutional review board) and use of informed consent, as appropriate. Retrospective studies require a statement regarding institutional review board approval. The current study was performed with the approval of the Ethics Committee of The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar Cancer Hospital. The animal experiments were strictly designed and performed according to the Guide for the Care and Use of Laboratory animals published by the US National Institutes of Health. Extensive efforts were made to ensure minimal suffering of the animals included in the study.

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Huang, L., Zhang, Y., Zhao, L. et al. Ferrostatin-1 Polarizes Microglial Cells Toward M2 Phenotype to Alleviate Inflammation After Intracerebral Hemorrhage. Neurocrit Care 36, 942–954 (2022). https://doi.org/10.1007/s12028-021-01401-2

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