Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice

被引：16

作者：

Chen, Tingting ^{[1
]}

Shi, Rubing ^{[1
]}

Suo, Qian ^{[1
]}

Wu, Shengju ^{[1
]}

Liu, Chang ^{[1
]}

Huang, Shuxian ^{[1
]}

Haroon, Khan ^{[1
]}

Liu, Ze ^{[1
]}

He, Yuyan ^{[1
]}

Tian, Heng-Li ^{[2
]}

Wang, Yongting ^{[1
]}

Tang, Yaohui ^{[1
]}

Yang, Guo-Yuan ^{[1
]}

Zhang, Zhijun ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai Jiao Tong Affiliated Peoples Hosp 6, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Neurosurg, Shanghai, Peoples R China

来源：

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM | 2023年 / 43卷 / 04期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

Brain; ferroptosis; GPX4; ischemic stroke; progranulin; CELL-DEATH; STROKE; NECROPTOSIS; INJURY;

D O I：

10.1177/0271678X221145090

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：505 / 517

页数：13

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