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Regulating PPARG Reduces Lipid Accumulation in Microglia and Promotes Functional Recovery After Spinal Cord Injury
Mingran Luo1,2, Jiayun Liu1,2, Yunxin Su1,2
1Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Abstract:
Spinal cord injury (SCI) substantially affects functional capacity and the immune system plays a crucial role in recovery. Examining alterations in microglia metabolism can lead to improved repair mechanisms; however, the molecular subtyping of microglia lacks consensus. In this study, the effects of SCI on macrophages and microglia in mice are investigated to identify tailored therapeutic targets and interventions for patients with SCI. Macrophages infiltrate the spinal cord shortly after injury; however, infiltration decreases over time. Microglial phagocytosis of myelin debris is associated with increased lipid accumulation. Macrophage deletion improves outcomes, whereas microglial deletion worsens them. The PLIN2+ microglia subtype in lipid droplet formation shows abnormal activation of the Pparg signaling pathway compared with that with other subtypes. PPARG promotes lipid metabolism and recovery, and atorvastatin (a PPARG agonist) reverses altered metabolic processes. Macrophages and microglia play complex roles in SCI. Targeting PPARG and its agonists is a promising therapeutic approach for SCI.
Insights
Spinal cord injury (SCI) recovery involves immune cells. Targeting the PPARG pathway in microglia shows promise for improving lipid metabolism and functional outcomes after SCI.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Spinal cord injury (SCI) significantly impairs function and involves complex immune responses.
- Microglia, the resident immune cells of the central nervous system, play a critical role in SCI recovery, but their metabolic subtypes and functions remain unclear.
- Understanding microglia and macrophage roles in SCI is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the dynamic roles of macrophages and microglia following SCI in mice.
- To identify specific microglia subtypes and metabolic pathways involved in SCI pathogenesis and repair.
- To explore potential therapeutic targets for enhancing recovery after SCI.
Main Methods:
- Investigated the infiltration and temporal dynamics of macrophages and microglia post-SCI in a mouse model.
- Analyzed microglial phagocytosis of myelin debris and associated lipid accumulation.
- Utilized genetic manipulation (macrophage and microglial deletion) to assess their specific contributions to SCI outcomes.
- Examined the role of the PLIN2+ microglia subtype and the peroxisome proliferator-activated receptor gamma (PPARG) signaling pathway.
Main Results:
- Macrophage infiltration into the spinal cord was transient, while microglia exhibited increased lipid accumulation due to myelin debris phagocytosis.
- Deletion of macrophages improved SCI outcomes, whereas deletion of microglia exacerbated them.
- A specific subtype, PLIN2+ microglia, showed abnormal activation of the PPARG pathway, linked to lipid metabolism.
- Activation of PPARG by its agonist, atorvastatin, reversed metabolic dysregulation and promoted recovery.
Conclusions:
- Macrophages and microglia exert complex, context-dependent effects on recovery from spinal cord injury.
- The PPARG signaling pathway and its agonists represent a promising therapeutic avenue for modulating microglia metabolism and improving SCI outcomes.
- Targeting lipid metabolism in microglia via PPARG agonists could be a viable strategy for SCI treatment.
