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Increases in miR-124-3p in Microglial Exosomes Confer Neuroprotective Effects by Targeting FIP200-Mediated Neuronal Autophagy Following Traumatic Brain Injury

  • Dai Li
  • Shan Huang
  • Zhenyu Yin
  • Jialin Zhu
  • Xintong Ge
  • Zhaoli Han
  • Jin Tan
  • Shishuang Zhang
  • Jing Zhao
  • Fanglian Chen
  • Haichen Wang
  • Ping LeiEmail author
Original Paper
  • 40 Downloads

Abstract

In our recent study, we observed consistent increases in miR-124-3p levels in exosomes derived from cultured BV2 microglia which was treated with repetitive traumatic brain injury (rTBI) mouse model brain extracts. To clarify the mechanisms underlying increases in microglia-derived exosomal miR-124-3p and their role in regulating neuronal autophagy after TBI, we investigated the impact of exosomal miR-124-3p on neuronal autophagy in scratch-injured HT22 neurons and rTBI mice. We harvested injured brain extracts from rTBI mice at 3 to 21 days post injury (DPI) for the treatment of cultured BV2 microglia in vitro. We observed significant induction of autophagy following TBI in vitro, and that inhibition of activated neuronal autophagy could protect against trauma-induced injury. Our results indicated that co-culture of injured HT22 neurons with miR-124-3p overexpressing BV2 microglia exerted a protective effect by inhibiting neuronal autophagy in scratch-injured neurons. Further research revealed that these effects were achieved mainly via upregulation of exosomal miR-124-3p, and that Focal adhesion kinase family-interacting protein of 200 kDa (FIP200) plays a key role in trauma-induced autophagy. Injection of exosomes into the vena caudalis in in vivo experiments revealed that exosomal miR-124-3p was associated with decreases in the modified neurological severity score (mNSS) and improvements in Morris water maze (MWM) test results in rTBI mice. Altogether, our results indicate that increased miR-124-3p in microglial exosomes following TBI may inhibit neuronal autophagy and protect against nerve injury via their transfer into neurons. Thus, treatment with microglial exosomes enriched with miR-124-3p may represent a novel therapeutic strategy for the treatment of nerve injury after TBI.

Keywords

Traumatic brain injury Exosomes Autophagy miRNA Microglia 

Notes

Acknowledgements

This research was supported by Grants from the National Natural Science Foundation of China (Grant Nos. 81772060, 81471252), Tianjin Science Foundation (Grant Nos. 16JCYBJC27200, 16JCQNJC11000, 16JCYBJC26900, 18ZXDBSY00090), Tianjin Medical University General Hospital Youth Cultivation Foundation (Grant Nos. ZYYFY2016001, ZYYFY2014025). The authors appreciate Li Liu, Weiyun Cui and Lei Zhou from Tianjin Neurological Institute for their technical support.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA) and approved by the Tianjin Medical University Animal Care and Use Committee (Permissions No. 011/2017).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Dai Li
    • 1
    • 2
  • Shan Huang
    • 1
    • 2
  • Zhenyu Yin
    • 1
    • 2
  • Jialin Zhu
    • 6
  • Xintong Ge
    • 1
    • 3
    • 4
    • 5
  • Zhaoli Han
    • 1
    • 2
  • Jin Tan
    • 1
    • 2
  • Shishuang Zhang
    • 1
    • 2
  • Jing Zhao
    • 1
    • 2
  • Fanglian Chen
    • 4
    • 5
  • Haichen Wang
    • 7
  • Ping Lei
    • 1
    • 2
    • 8
    Email author
  1. 1.Laboratory of Neuro-Trauma and Neurodegenerative Disorders, Tianjin Geriatrics InstituteTianjin Medical University General HospitalTianjinChina
  2. 2.Department of GeriatricsTianjin Medical University General HospitalTianjinChina
  3. 3.Department of NeurosurgeryTianjin Medical University General HospitalTianjinChina
  4. 4.Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological InstituteTianjin Medical University General HospitalTianjinChina
  5. 5.Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous SystemMinistry of EducationTianjinChina
  6. 6.Department of Ultrasound Diagnosis and TreatmentTianjin Medical University Cancer Institute and HospitalTianjinChina
  7. 7.Department of NeurologyDuke University Medical CenterDurhamUSA
  8. 8.Laboratory of Neuro-Trauma and Neurodegenerative Disorders, Tianjin Geriatrics Institute, Department of GeriatricsTianjin Medical University General HospitalTianjinChina

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