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Neurochem Res. 2019 Jan 9. doi: 10.1007/s11064-018-02714-z. [Epub ahead of print]

MiR-124 Enriched Exosomes Promoted the M2 Polarization of Microglia and Enhanced Hippocampus Neurogenesis After Traumatic Brain Injury by Inhibiting TLR4 Pathway.

Yang Y1,2, Ye Y1,3, Kong C1, Su X1, Zhang X1, Bai W1, He X4.

Author information

1
Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an, 710032, China.
2
Department of Neurosurgery, PLA 422nd Hospital, Zhanjiang, 524005, China.
3
Department of Neurosurgery, PLA 163rd Hospital (Second Affiliated Hospital of Hunan Normal University), Changsha, 410000, China.
4
Department of Neurosurgery, Xijing Hospital, Airforce Military Medical University (Fourth Military Medical University), Xi'an, 710032, China. hexiaos@fmmu.edu.cn.

Abstract

MicroRNA-124 (miR-124) is a brain specific miRNA that is highly expressed in microglia. The upregulation of miR-124 contributes to M2 polarization of microglia, which is beneficial to neurogenesis. Exosomes are lipid membrane vesicles that can deliver miR-124 into the brain. However, whether miR-124 enriched exosomes (Exo-miR-124) can regulate the polarization of microglia and affect hippocampus neurogenesis after traumatic brain injury (TBI) is unknown. To clarify this, the Exo-miR-124 was first constructed, and then was intravenously administrated into rats via tail vein with the dose of 3 × 109 particles/each rat at 24 h post TBI. The polarization of microglia in hippocampus was evaluated through measuring the signature genes and cytokines of M1/M2 phenotype by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immune sorbent assay (ELISA) at 7/14/21/28 days after TBI. Hippocampus neurogenesis was evaluated through detecting the proliferation marker BrdU/SOX2 and differentiation marker BrdU/NeuN by immunofluorescence (IF) at 7 and 28 days after TBI respectively. Neurological function was evaluated by neurological severity score (NSS) and morris water maze (MWM) at 7/14/21/28 and 24-28 days after TBI respectively. To explore the underlying mechanisms, the mRNA expression of TLR4 pathway molecules in hippocampus were measured by RT-PCR, and the polarization of microglia and the activation of TLR4 pathway in BV2 cells were measured after exosome treatment as well. Results demonstrated that Exo-miR-124 treatment promoted the M2 polarization of microglia, enhanced neurogenesis in hippocampus, and improved function recovery after TBI. The M2 polarization effect of Exo-miR-124 was produced through inhibiting TLR4 pathway, which was verified in hippocampus and BV2 microglia. In conclusion, Exo-miR-124 treatment promoted M2 polarization of microglia and improved hippocampal neurogenesis and functional recovery after brain injury, which might be a strategy to improve the outcome of TBI.

KEYWORDS:

Exosome; MiR-124; Microglia; Neurogenesis; TLR4; Traumatic brain injury

PMID:
30628018
DOI:
10.1007/s11064-018-02714-z

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