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Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice
Tingting Chen1, Rubing Shi1, Qian Suo1
1Shanghai Jiao Tong Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
The cellular redox state is essential for inhibiting ferroptosis. Progranulin (PGRN) plays an important role in maintaining the cellular redox state after ischemic brain injury. However, the effect of PGRN on ferroptosis and its underlying mechanism after cerebral ischemia remains unclear. This study assesses whether PGRN affects ferroptosis and explores its mechanism of action on ferroptosis after cerebral ischemia. We found endogenous PGRN expression in microglia increased on day 3 after ischemia. In addition, PGRN agonists chloroquine and trehalose upregulated PGRN expression, reduced brain infarct volume, and improved neurobehavioral outcomes after cerebral ischemia compared to controls (p < 0.05). Moreover, PGRN upregulation attenuated ferroptosis by decreasing malondialdehyde and increasing Gpx4, Nrf2, and Slc7a11 expression and glutathione content (p < 0.05). Furthermore, chloroquine induced microglial lysosome PGRN release, which was associated with increased neuron survival. Our results indicate that PGRN derived from microglial lysosomes effectively inhibits ferroptosis during ischemic brain injury, identifying it as a promising target for ischemic stroke therapy.
Insights
Progranulin (PGRN) inhibits ferroptosis after ischemic brain injury by regulating cellular redox state. PGRN, released from microglial lysosomes, reduces brain damage and improves outcomes, offering a therapeutic target for ischemic stroke.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Cellular redox state is critical for preventing ferroptosis.
- Progranulin (PGRN) influences cellular redox balance post-ischemic brain injury.
- The precise role and mechanism of PGRN in ferroptosis following cerebral ischemia are not fully understood.
Purpose of the Study:
- To investigate the effect of PGRN on ferroptosis after cerebral ischemia.
- To elucidate the underlying molecular mechanisms of PGRN's action on ferroptosis in this context.
Main Methods:
- Assessed endogenous PGRN expression in microglia post-ischemia.
- Administered PGRN agonists (chloroquine, trehalose) to evaluate effects on infarct volume and neurobehavior.
- Quantified ferroptosis markers including malondialdehyde, Gpx4, Nrf2, Slc7a11 expression, and glutathione content.
- Investigated PGRN release from microglial lysosomes.
Main Results:
- Endogenous PGRN expression in microglia increased by day 3 post-ischemia.
- PGRN agonists reduced brain infarct volume and improved neurobehavioral outcomes.
- Upregulated PGRN attenuated ferroptosis, evidenced by decreased malondialdehyde and increased Gpx4, Nrf2, Slc7a11, and glutathione.
- Chloroquine-induced microglial lysosomal PGRN release correlated with enhanced neuron survival.
Conclusions:
- Microglial-derived PGRN, released from lysosomes, effectively inhibits ferroptosis in ischemic brain injury.
- PGRN represents a potential therapeutic target for mitigating damage in ischemic stroke.
