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Deferoxamine Induces Autophagy Following Traumatic Brain Injury via TREM2 on Microglia

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Abstract

Previous studies have indicated that iron disorder, inflammation, and autophagy play an important role in traumatic brain injury (TBI). The triggering receptor expressed on myeloid cells 2 (TREM2), an immunoglobulin superfamily transmembrane receptor, is involved in inflammation. However, the role of TREM2 in modulating the microglia response in TBI has been rarely investigated. The present study aimed to investigate if the iron chelator deferoxamine (DFO) could ameliorate TBI through autophagy mediated by the TREM2. TBI was developed by the controlled cortical impact (CCI) mouse model and stretching of individual primary cortical microglia taken from the tissue of the rat brain. DFO was intraperitoneally used for intervention. Western blotting assay, qRT-PCR, TUNEL staining, immunofluorescence staining, confocal microscopy analysis, transmission electron microscopy, H&E staining, brain water content measurement, and the neurobehavioral assessments were performed. TREM2 expression was up-regulated in cortex of TBI mice model and in microglia stretching model, which was attenuated by DFO. After the mice were subjected to CCI, DFO treatment significantly up-regulated the protein levels of autophagy compared with the TBI group at 3 days and caused an increase of autophagic vacuoles. Treatment with DFO reduced TBI-induced cell apoptosis, cerebral edema, neuroinflammation, and motor function impairment in mice, at least partly via the mTOR signaling pathway that facilitates the TREM2 activity. The results indicated that the maintenance of iron homeostasis by DFO plays neuroprotection by modulating the inflammatory response to TBI through TREM2-mediated autophagy. This study suggested that TREM2-mediated autophagy might be a potential target for therapeutic intervention in TBI.

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Data availability

The data that support the findings of this study are available on request from the corresponding author.

Abbreviations

CNS:

Central nervous system

CCI:

Controlled cortical impact

DPI:

Days post-injury

DFO:

Deferoxamine

Iba-1:

Ionized calcium-binding adaptor molecule 1

IL-1β:

Interleukin-1 beta

IL-4:

Interleukin-4

IL-6:

Interleukin-6

mTOR:

Mammalian target of rapamycin

mNSS:

Modified neurological severity scores

qRT-PCR:

Quantitative real-time polymerase chain reaction

SI:

Stretch injury

TUNEL:

TdT-mediated dUTP nick end labeling

TBI:

Traumatic brain injury

TREM2:

Triggering receptor expressed on myeloid cells 2

TNF-α:

Tumor necrosis factor-alpha

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Funding

This work was supported by the Science and Technology Commission of Shanghai Municipality under the Natural Science Foundation of Shanghai [19ZR1438600 and 21142202100].

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Author notes

  1. Chunhao Zhang and Chen Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Chunhao Zhang, Chen Xu, Yao Jing, Heli Cao, Xuyang Wang, Jianwei Zhao, Qiuyuan Gong & Shiwen Chen

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  1. Chunhao Zhang
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Contributions

Chen, SW conceived of the research and revised the manuscript. Zhang, CH and Xu, C performed the experiments and collected the data. Cao, HL, Jing, Y, and Wang, XY were responsible for the data analysis. Zhao, JW and Gong, QY prepared materials. Zhang, CH and Xu, C wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shiwen Chen.

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This study was approved by the Animal Ethics Committee of the Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine for the care and use of experimental animals.

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Zhang, C., Xu, C., Jing, Y. et al. Deferoxamine Induces Autophagy Following Traumatic Brain Injury via TREM2 on Microglia. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03875-x

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