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LncRNA AP000654.1 attenuates cerebral ischemia-reperfusion injury by regulating mitophagy-mediated NLRP3 inflammasome
Chi Zhang1, Yixiang Cui1, Zhaojing Zhang1
1Department of Medical Genetics and Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
Background:
Ischemic stroke (IS) remains a leading cause of disability worldwide, and its therapeutic window is very narrow. Ischemia-reperfusion injury exacerbates secondary brain damage. Microglial NLRP3 inflammasome activation drives neuroinflammation, yet its upstream regulation requires further elucidation. We previously identified lncRNA AP000654.1 as significantly downregulated in the peripheral blood of stroke patients, prompting our investigation into its potential role in microglial biology.
Methods:
Using an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model in HMC3 human microglial cells, we investigated the role of lncRNA AP000654.1-previously identified as significantly downregulated in peripheral blood of stroke patients-in regulating microglial inflammatory responses.
Results:
OGD/R treatment upregulated NLRP3 inflammasome-related genes, induced pyroptosis-associated changes, and altered mitophagy markers. LncRNA AP000654 0.1 overexpression suppressed this excessive mitophagy by inhibiting the PINK1-Parkin pathway, thereby improving mitochondrial function. This suppression subsequently attenuated NLRP3 inflammasome assembly and pyroptosis. Crucially, enforcing mitophagy with rapamycin exacerbated the injury, which was effectively rescued by lncRNA AP000654.
Conclusion:
LncRNA AP000654.1 is associated with suppression of excessive mitophagy-assocated mitochondrial stress and NLRP3 inflammasome activation in microglia, suggesting its potential relevance as a therapeutic target in ischemic stroke.
Insights
Long non-coding RNA AP000654.1 suppresses excessive mitophagy and NLRP3 inflammasome activation in microglia, offering a potential therapeutic target for ischemic stroke (IS) and reducing brain damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Ischemic stroke (IS) is a major cause of disability with a narrow therapeutic window.
- Ischemia-reperfusion injury worsens secondary brain damage.
- Microglial NLRP3 inflammasome activation drives neuroinflammation, but its upstream regulation is unclear.
Purpose of the Study:
- Investigate the role of downregulated lncRNA AP000654.1 in microglial inflammatory responses.
- Elucidate the mechanism by which lncRNA AP000654.1 regulates mitophagy and inflammasome activation.
Main Methods:
- Utilized an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model in HMC3 human microglial cells.
- Assessed NLRP3 inflammasome-related genes, pyroptosis markers, and mitophagy markers.
- Manipulated lncRNA AP000654.1 expression and mitophagy using rapamycin.
Main Results:
- OGD/R upregulated NLRP3 inflammasome genes, induced pyroptosis, and altered mitophagy.
- LncRNA AP000654.1 overexpression inhibited the PINK1-Parkin pathway, suppressed excessive mitophagy, improved mitochondrial function, and attenuated NLRP3 inflammasome activation and pyroptosis.
- Forced mitophagy exacerbated injury, but lncRNA AP000654.1 rescued this effect.
Conclusions:
- LncRNA AP000654.1 suppresses excessive mitophagy-associated mitochondrial stress and NLRP3 inflammasome activation in microglia.
- LncRNA AP000654.1 shows potential as a therapeutic target for ischemic stroke.
