miR-223 accelerates lipid droplets clearance in microglia following spinal cord injury by upregulating ABCA1.

Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2003-

Spinal Cord Injuries*/metabolism ; Spinal Cord Injuries*/pathology ; MicroRNAs*/metabolism ; MicroRNAs*/genetics ; Microglia*/metabolism ; Microglia*/pathology ; ATP Binding Cassette Transporter 1*/metabolism ; ATP Binding Cassette Transporter 1*/genetics ; Lipid Droplets*/metabolism ; Up-Regulation* ; Mice, Inbred C57BL*; Animals ; Mice ; Cell Line ; Male ; Lipid Metabolism/genetics

Background: Spinal cord injury (SCI) is characterized by extensive demyelination and inflammatory responses. Facilitating the clearance of lipid droplets (LDs) within microglia contributes to creating a microenvironment that favors neural recovery and provides essential materials for subsequent remyelination. Therefore, investigating MicroRNAs (miRNAs) that regulate lipid homeostasis after SCI and elucidating their potential mechanisms in promoting LDs clearance in microglia have become focal points of SCI research.
Methods: We established a subacute C5 hemicontusion SCI model in mice and performed transcriptomic sequencing on the injury epicenter to identify differentially expressed genes and associated pathways. Confocal imaging was employed to observe LDs accumulation. Multi-omics analyses were conducted to identify differentially expressed mRNA and miRNA post-SCI. Pathway enrichment analysis and protein-protein interaction network construction were performed using bioinformatics methods, revealing miR-223-Abca1 as a crucial miRNA-mRNA pair in lipid metabolism regulation. BV2 microglia cell lines overexpressing miR-223 were engineered, and immunofluorescence staining, western blot, and other techniques were employed to assess LDs accumulation, relevant targets, and inflammatory factor expression, confirming its role in regulating lipid homeostasis in microglia.
Results: Histopathological results of our hemicontusion SCI model confirmed LDs aggregation at the injury epicenter, predominantly within microglia. Our transcriptomic analysis during the subacute phase of SCI in mice implicated ATP-binding cassette transporter A1 (Abca1) as a pivotal gene in lipid homeostasis, cholesterol efflux and microglial activation. Integrative mRNA-miRNA multi-omics analysis highlighted the crucial role of miR-223 in the neuroinflammation process following SCI, potentially through the regulation of lipid metabolism via Abca1. In vitro experiments using BV2 cells overexpressing miR-223 demonstrated that elevated levels of miR-223 enhance ABCA1 expression in myelin debris and LPS-induced BV2 cells. This promotes myelin debris degradation and LDs clearance, and induces a shift toward an anti-inflammatory M2 phenotype.
Conclusions: In summary, our study unveils the critical regulatory role of miR-223 in lipid homeostasis following SCI. The mechanism by which this occurs involves the upregulation of ABCA1 expression, which facilitates LDs clearance and myelin debris degradation, consequently alleviating the lipid burden, and inhibiting inflammatory polarization of microglia. These findings suggest that strategies to enhance miR-223 expression and target ABCA1, thereby augmenting LDs clearance, may emerge as appealing new clinical targets for SCI treatment.
(© 2024. The Author(s).)

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81972064 National Natural Science Foundation of China; 81902217 National Natural Science Foundation of China; 2023A1515010565 Natural Science Foundation of Guangdong Province; 2020A1515011415 Natural Science Foundation of Guangdong Province

Keywords: ATP-binding cassette transporter A1 (ABCA1); Lipid droplets; Microglia; Spinal cord injury (SCI); miR-223

0 (MicroRNAs)
0 (ATP Binding Cassette Transporter 1)
0 (MIRN223 microRNA, mouse)
0 (Abca1 protein, mouse)

Date Created: 20240715 Date Completed: 20240716 Latest Revision: 20240813

20240813

PMC11247820

10.1186/s12967-024-05480-5

39010173