Bioinformatics analysis identiﬁed apolipoprotein E as a hub gene regulating neuroinﬂammation in macrophages and microglia following spinal cord injury

Frontiers in Immunology, 2022 · DOI: 10.3389/fimmu.2022.964138 · Published: August 24, 2022

Simple Explanation

Following a spinal cord injury (SCI), macrophages and microglia are key players in the resulting chronic neuroinflammation. These cells have similar functions, but their ability to remove debris and maintain balance differs. Using bioinformatics analysis, the study pinpointed apolipoprotein E (APOE) as a central gene in both macrophages and microglia during the subacute and chronic phases of SCI. The study then confirmed these findings in a mouse model of cervical spinal cord injury, observing myelin uptake, lipid droplets, and lysosome accumulation in these immune cells. Furthermore, the study found that when APOE was removed, the mice experienced worsened neurological function, increased neuroinflammation and greater loss of white matter. These findings suggest that targeting APOE and the related cholesterol pathways could be a potential therapeutic approach to reduce neuroinflammation and enhance recovery after SCI.

Study Duration

Not specified

Participants

Eight-week-old wild-type and APOE-/- male mice

Evidence Level

Original Research

Key Findings

1
APOE was identified as a hub gene in both macrophages and microglia during the subacute and chronic phases of SCI.
2
Histopathological analysis revealed the accumulation of lipid droplets and lysosomes in both macrophages and microglia after SCI.
3
APOE knockout mice showed worse functional recovery, increased neuroinflammation, and exacerbated white matter loss after spinal cord injury.

Research Summary

This study aimed to identify key genes and pathways activated in macrophages and microglia during the subacute and chronic phases of SCI using bioinformatics analysis of the scRNA-seq dataset GSE159638. The researchers validated the bioinformatics results through histological analysis of a mouse model of cervical spinal cord hemi-contusion and by analyzing the effect of APOE knockout on neurological function. The study concludes that targeting APOE and related cholesterol efflux may be a promising strategy for reducing neuroinflammation and promoting recovery following SCI.

Practical Implications

Therapeutic Target Identification

APOE and associated cholesterol efflux pathways represent a potential therapeutic target for reducing neuroinflammation following SCI.

Understanding Immune Response

The study enhances the understanding of the roles of macrophages and microglia, and their lipid metabolism, in the progression of SCI.

Future Research Directions

Further investigation is needed to explore stimulation of reverse cholesterol transport and detailed molecular mechanisms of APOE in SCI.

Study Limitations

1
Small sample sizes at 21 dpi and absence of macrophages in sham samples potentially introduce bias.
2
Validation was performed using wild-type and APOE-/- spinal cord contusion injury mouse models, without exogenous APOE treatment.
3
APOE-/- knockout is not myeloid-specific, and the molecular mechanisms underlying the phenotypes of APOE-/- mice have not been fully elucidated.

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