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Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
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Netrin-1 controls inflammation in response to ischemic stroke through altering microglia phenotype
Xiaosheng Yang1, Yang Liu2, Weijie Zhong1
1Department of Neurosurgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Frontiers in Immunology
|June 30, 2023
Summary
Targeting microglial Netrin-1 with its receptor UNC5a shifts microglia to an anti-inflammatory state, protecting neurons in ischemic stroke. This offers a promising therapeutic strategy for stroke recovery.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Current ischemic stroke treatments have limitations in targeting, efficacy, and side effects.
- New strategies are needed to improve neuronal survival and regeneration after stroke.
- The role of microglial Netrin-1 in ischemic stroke remains incompletely understood.
Purpose of the Study:
- To investigate the role of microglial Netrin-1 in ischemic stroke.
- To analyze Netrin-1 and its receptor expression in cerebral microglia.
- To evaluate the therapeutic potential of targeting microglial Netrin-1.
Main Methods:
- Examined Netrin-1 and receptor expression in human and animal stroke models.
- Utilized RNA sequencing data from a rat middle cerebral artery occlusion model.
- Employed microglia-specific gene targeting and blood-brain barrier-penetrant delivery in mice.
- Analyzed microglial phenotype, apoptosis, and migration in response to Netrin-1 signaling.
Main Results:
- Netrin-1 receptor signaling, primarily via UNC5a, was activated in microglia.
- Activation shifted microglia to an anti-inflammatory (M2-like) phenotype.
- This shift reduced microglial apoptosis and migration.
- Netrin-1-induced microglial changes provided neuroprotection in vivo.
Conclusions:
- Microglial Netrin-1 signaling, particularly through UNC5a, promotes neuroprotection in ischemic stroke.
- Targeting Netrin-1 and its receptors represents a potential therapeutic avenue.
- This strategy may enhance post-ischemic neuronal survival and functional recovery.
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