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Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons

Huang, Shan, Ge, Xintong, Yu, Jinwen, Han, Zhaoli, Yin, Zhenyu, Li, Ying, Chen, Fanglian, Wang, Haichen, Zhang, Jianning, Lei, Ping·2018·The FASEB Journal
DOI 10.1096/fj.201700673r
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Abstract

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neu‐ronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR‐124‐3p increased most apparently in the miRNAs. We found that miR‐124‐3p promoted the anti‐inflamed M2 polarization in microglia, and microglial exosomal miR‐124‐3p inhibited neuronal inflammation in scratch‐injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR‐124‐3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR‐124‐3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR‐124‐3p by pathway analysis. We proved that it was directly targeted by miR‐124‐3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR‐124‐3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR‐124‐3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreasedexpressiononRhoAand neurodegenerative proteins [Aß‐peptide and p‐Tau]. It also improved the neurologic outcome and inhibited neuro‐inflammation in mice with rTBI. Taken together, increased miR‐124‐3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR‐124‐3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR‐124‐3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.—Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J. 32, 512‐528 (2018). www.fasebj.org

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Metadata

Authors
Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., & Lei, P.
Affiliations
  • Laboratory of Neuro‐Trauma and Neurodegenerative Disorders Tianjin Geriatrics Institute Tianjin China
  • Key Laboratory of Injuries, Variations, and Regeneration of Nervous System Tianjin Neurological Institute, Tianjin Medical University General Hospital Tianjin China
  • Department of Neurology Duke University Medical Center Durham North Carolina USA
Venue
The FASEB Journal
Publisher
Wiley
Published
2017-09-21
Volume
32
Issue
1
Pages
512-528
ISSN
  • 0892-6638
  • 1530-6860
DOI
10.1096/fj.201700673r
Cited by
388
References
9
Language
en
Update notices
erratum (2018-03-29)
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders
  • National Natural Science Foundation of China (81501055, 81471252, 81772060)
  • Tianjin Science and Technology Committee (13JCYBJC23700)

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