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S100A8 regulates autophagy-dependent ferroptosis in microglia after experimental subarachnoid hemorrhage
Qianke Tao1, Xiancheng Qiu1, Chaojie Li1
1Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Laboratory of Neurological Diseases and Brain Function, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.
Abstract:
Targeting microglial activation has been shown to ameliorate early brain injury (EBI) after subarachnoid hemorrhage (SAH). Ferroptosis is a new form of programmed cell death after SAH, but these molecular features were not recognized as evidence of microglial function so far. In this study, we constructed microglial S100A8-specific knockdown and established the SAH model in vivo and in vitro. Multi-technology strategies, including high throughput sequencing, adeno-associated virus gene gene-editing and several molecular biotechnologies to validate the effects of S100A8 on microglial autophagy and ferroptosis after SAH. Our results revealed that the expression of S100A8 was significantly increased in brain tissue after SAH. Targeted microglial S100A8 inhibition improved neural function and neuronal apoptosis in mice after SAH. Further mechanism exploration found that favourable effects of S100A8 depletion in EBI may be through the inhibition of microglia autophagy-dependent ferroptosis. In conclusion, S100A8 may be a potential intervention target for microglial ferroptosis in EBI after SAH.
Insights
Targeting S100A8 in microglia may treat early brain injury after subarachnoid hemorrhage. Inhibiting S100A8 reduces microglial ferroptosis and improves neural function, offering a new therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Microglial activation contributes to early brain injury (EBI) following subarachnoid hemorrhage (SAH).
- Ferroptosis, a form of programmed cell death, is implicated in SAH, but its link to microglial function remains unclear.
- S100A8 expression increases in the brain post-SAH.
Purpose of the Study:
- To investigate the role of S100A8 in microglial function after SAH.
- To determine if targeting S100A8 affects autophagy-dependent ferroptosis in microglia.
- To evaluate S100A8 as a potential therapeutic target for EBI.
Main Methods:
- Established SAH models in vivo and in vitro.
- Constructed microglial S100A8-specific knockdown models.
- Utilized high-throughput sequencing, adeno-associated virus gene editing, and molecular biotechnologies.
Main Results:
- S100A8 expression was significantly elevated in brain tissue after SAH.
- Targeted inhibition of microglial S100A8 improved neural function and reduced neuronal apoptosis in SAH mice.
- S100A8 depletion ameliorated EBI by inhibiting autophagy-dependent ferroptosis in microglia.
Conclusions:
- S100A8 plays a critical role in regulating microglial autophagy-dependent ferroptosis after SAH.
- Inhibiting microglial S100A8 shows therapeutic potential for mitigating EBI.
- S100A8 represents a promising intervention target for ferroptosis in EBI post-SAH.
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