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Updated: May 2, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Per2 deficiency in microglia alleviates motor dysfunction by inhibiting ferroptosis in spinal cord injury
Pengfei Bie1,2, Dongpo Su1, Yang Gao1,2
1The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, PR China.
Abstract:
Microglia play significant roles in spinal cord injury (SCI) progression. Previous studies have suggested that ferroptosis plays a crucial role in exacerbating neuronal death following SCI; however, the role of microglial ferroptosis in SCI and the underlying mechanisms remain elusive. Here, we elucidate that lipid droplets accumulate in microglia to facilitate microglial ferroptosis after SCI. Notably, microglial ferroptosis peaks at 3 days post-injury, after which it decreases. Microglial Period 2 (Per2) expression is elevated after SCI in vivo; this change is highly synchronized with the changes in microglial ferroptosis. Microglia-specific Per2 knockout promoted neurological function recovery by suppressing microglial ferroptosis. In vitro, Per2 overexpression and deficiency amplified and mitigated microglial ferroptosis, respectively. RNA-seq indicated that Gpx4 was downregulated by Per2. Coimmunoprecipitation demonstrated that Per2 directly interacted with PPARα. Overall, our results indicate that Per2 determines the susceptibility of microglial ferroptosis via the PPARα-Gpx4 axis after SCI.
Insights
Microglial ferroptosis, a cell death process, worsens spinal cord injury (SCI). Period 2 (Per2) protein regulates this process via the PPARα-Gpx4 pathway, offering a potential therapeutic target for SCI recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key immune cells in the central nervous system.
- Spinal cord injury (SCI) involves significant neuronal damage.
- Ferroptosis, an iron-dependent cell death, contributes to neuronal loss in SCI.
Purpose of the Study:
- Investigate the role and mechanisms of microglial ferroptosis in SCI.
- Identify molecular regulators of microglial ferroptosis post-SCI.
Main Methods:
- Animal models of SCI.
- In vitro cell culture experiments.
- RNA sequencing (RNA-seq) and coimmunoprecipitation.
Main Results:
- Lipid droplet accumulation and ferroptosis were observed in microglia after SCI.
- Microglial ferroptosis peaked at 3 days post-injury.
- Microglial Period 2 (Per2) expression increased post-SCI and correlated with ferroptosis.
- Per2 knockout in microglia improved neurological recovery by reducing ferroptosis.
- Per2 regulated ferroptosis by downregulating Gpx4 via interaction with PPARα.
Conclusions:
- Microglial ferroptosis is a significant contributor to SCI progression.
- Period 2 (Per2) protein acts as a key regulator of microglial ferroptosis.
- The Per2-PPARα-Gpx4 axis represents a potential therapeutic target for SCI treatment.
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