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Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke

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Abstract

Microglia and astrocytes are key players in neuroinflammation and ischemic stroke. A1 astrocytes are a subtype of astrocytes that are extremely neurotoxic and quickly kill neurons. Although the detrimental A1 astrocytes are present in many neurodegenerative diseases and are considered to accelerate neurodegeneration, their role in the pathophysiology of ischemic stroke is poorly understood. Here, we combined RNA-seq, molecular and immunological techniques, and behavioral tests to investigate the role of A1 astrocytes in the pathophysiology of ischemic stroke. We found that astrocyte phenotypes change from a beneficial A2 type in the acute phase to a detrimental A1 type in the chronic phase following ischemic stroke. The activated microglial IL1α, TNF, and C1q prompt commitment of A1 astrocytes. Inhibition of A1 astrocytes induction attenuates reactive gliosis and ameliorates morphological and functional defects following ischemic stroke. The crosstalk between astrocytic C3 and microglial C3aR contributes to the formation of A1 astrocytes and morphological and functional defects. In addition, NF-κB is activated following ischemic stroke and governs the formation of A1 astrocytes via direct targeting of inflammatory cytokines and chemokines. Taken together, we discovered that A2 astrocytes and A1 astrocytes are enriched in the acute and chronic phases of ischemic stroke respectively, and that the C3/C3aR/NF-κB signaling leads to A1 astrocytes induction. Therefore, the C3/C3aR/NF-κB signaling is a novel therapeutic target for ischemic stroke treatment.

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Data Availability

All data used in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Dong Zhang and Dr. Dan Tian for their technical assistance in flow cytometry. Figure 1A was drawn by Adobe Illustrator. Figure 10 was adapted from “Activated Astrocytes and Microglia Release Proinflammatory Cytokines and Induce Neurodegeneration,” by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82201622) and the Natural Science Foundation of Inner Mongolia (No. 2020MS03017).

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Authors and Affiliations

  1. Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Song Wang, Yuhualei Pan, Yushang Zhao, Huan Wang, Song Zhang & Jingyi Yao

  2. Beijing Clinical Research Institute, Beijing, 100050, China

    Song Wang, Yuhualei Pan, Yushang Zhao, Huan Wang, Song Zhang & Jingyi Yao

  3. Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Chengjie Zhang, Huixuan Ma, Jinmei Sun, Dan Xie & Yongbo Zhang

  4. Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Yuhualei Pan

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Contributions

Song Wang, Dan Xie, and Yongbo Zhang designed and supervised the study. Yuhualei Pan, Yushang Zhao, Huan Wang, and Hhuixuan Ma created focal ischemic stroke mice. Song Wang performed the bioinformatics analysis, real-time PCR verifications, behavioral tests, immunofluorescent staining, and CUT&Tag. Chengjie Zhang performed RNA-seq experiments. Jinmei Sun and Song Zhang analyzed the data from behavioral tests. Yuhualei Pan and Jingyi Yao performed the flow cytometry experiments. Song Wang, Dan Xie, and Yongbo Zhang wrote and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Song Wang, Dan Xie or Yongbo Zhang.

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Wang, S., Pan, Y., Zhang, C. et al. Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04210-8

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