Dataset Information

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

ABSTRACT: Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; however, the mechanisms and potential role of interactions between the microglia/macrophages and OPCs are poorly understood. Here, we generated a transcriptional profile of exosomes from activated microglia, and found that miR-615-5p was elevated. miR-615-5p bound to 3'UTR of myelin regulator factor (MYRF), a crucial myelination transcription factor expressed in oligodendrocyte lineage cells. Mechanistically, exosomes from activated microglia transferred miR-615-5p to OPCs, which directly bound to MYRF and inhibited OPC maturation. Furthermore, an effect of AAV expressing miR-615-5p sponge in microglia was tested in experimental autoimmune encephalomyelitis (EAE) and cuprizone (CPZ)-induced demyelination model, the classical mouse models of multiple sclerosis. miR-615-5p sponge effectively alleviated disease progression and promoted remyelination. This study identifies miR-615-5p/MYRF as a new target for the therapy of demyelinating diseases.

SUBMITTER: Ji XY

PROVIDER: S-EPMC10801965 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Ji Xiao-Yu XY Guo Yu-Xin YX Wang Li-Bin LB Wu Wen-Cheng WC Wang Jia-Qi JQ He Jin J Gao Rui R Rasouli Javad J Gao Meng-Yuan MY Wang Zhen-Hai ZH Xiao Dan D Zhang Wei-Feng WF Ciric Bogoljub B Zhang Yuan Y Li Xing X

Journal of neuroinflammation 20240122 1

Demyelination and failure of remyelination in the central nervous system (CNS) characterize a number of neurological disorders. Spontaneous remyelination in demyelinating diseases is limited, as oligodendrocyte precursor cells (OPCs), which are often present in demyelinated lesions in abundance, mostly fail to differentiate into oligodendrocytes, the myelinating cells in the CNS. In addition to OPCs, the lesions are assembled numbers of activated resident microglia/infiltrated macrophages; howev ...[more]

PMID: 38246987

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Project description:BackgroundNeuroinflammation plays a crucial role in the repair of spinal cord injury (SCI), with microglia, pivotal in neuroinflammation, driving either degeneration or recovery in this pathological process. Recently, plasma-derived exosomes (denoted Exos) have presented a high capacity for promoting functional recovery of SCI through the anti-inflammatory effects, and pretreated exosomes are associated with better outcomes. Thus, we aimed to explore whether melatonin-pretreated plasma-derived exosomes (denoted MExo) could exert superior effects on SCI, and attempted to elucidate the potential mechanisms.MethodsElectron microscopy, nanoparticle tracking analysis, and western blot were applied to delineate the distinctions between Exos and MExos. To assess their therapeutic potentials, we established a contusion SCI rat model, complemented by a battery of in vitro experiments comparing both groups. Subsequently, a miRNA microarray analysis was conducted, followed by a series of rescue experiments to elucidate the specific role of miRNAs in MExos. To further delve into the molecular mechanisms involved, we employed western blot analysis and the luciferase reporter gene assay.ResultsMelatonin promoted the release of exosome from plasma, concurrently amplifying their anti-inflammatory properties. Furthermore, it was discerned that MExos facilitated a transition in microglia polarization from M1 to M2 phenotype, a phenomenon more pronounced than that observed with Exos. In an endeavor to elucidate this variance, we scrutinized miRNAs exhibiting elevated expression levels in MExos, pinpointing miR-138-5p as a pivotal element in this dynamic. Following this, an in-depth investigation into the role of miR-138-5p was undertaken, which uncovered its efficacy in driving phenotypic alterations within microglia. The analysis of downstream genes targeted by miR-138-5p revealed that it exerted a negative regulatory influence on SOX4, which was found to obstruct the generation of M2-type microglia and the secretion of anti-inflammatory cytokines, thereby partially elucidating the mechanism behind miR-138-5p's regulation of microglia polarization.ConclusionsWe innovatively observed that melatonin enhanced the anti-inflammatory function of Exos, which further decreased the expression of SOX4 by delivering miR-138-5p. This inhibition promoted the conversion of M1 microglia to M2 microglia, thus offering a viable option for the treatment of SCI.The translational potential of this articleThis study highlights that melatonin enhances the anti-inflammatory function of Exos through delivery of miR-138-5p. Activation of miR-138-5p/SOX4 axis by engineered melatonin-pretreated plasma exosomes may be a potential target for SCI treatment.

Project description:BackgroundChronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model.MethodsC57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms.ResultsHuc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy.ConclusionHuc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis.

Dataset Information

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

Publications

Microglia-derived exosomes modulate myelin regeneration via miR-615-5p/MYRF axis.

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