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Published on: January 30, 2014
Astrocytic ET-1 System Determines Microglia Phenotype Following Spinal Cord Injury
Bingqiang He1,2, Si Xu1, Mengdi Li1
1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, P.R. China.
Abstract:
Microglia/macrophages accumulate at the lesion site by switching toward pro-inflammatory (M1)-dominant phenotype at the acute phase following spinal cord injury (SCI). Such biased polarization shapes the functional outcomes by expanding tissue damage. In the present study, the astrocytic endothelin-1 (ET-1) system is revealed to be immediately activated after SCI, driving microglia polarization toward M1, but suppressing toward M2 phenotype through activation of transcription coactivator YAP via ETA and ETB receptors. In addition, the activation of astrocytic ET-1 system results in elevation of blood plasma ET-1 level, suggesting a high diagnostic value. SCI-induced thrombin is pinpointed as a crucial activator of the astrocytic ET-1 system. The serine protease dramatically promotes the astrocytic expression of preproendothelin-1 (ppET-1) through protease-activated receptor-1 (PAR-1)/RhoA/NF-κB and PAR-1/MAPKs/NF-κB signal pathways. Meanwhile, it induces the expression of astrocytic endothelin-converting enzyme 1 (ECE-1) responsible for mature ET-1 processing. Pharmacological inhibitors of PAR-1 and ET-1 are shown to be highly efficient in microglia M1 phenotype reversion and favorable for the recovery of rat locomotor function after SCI. The findings have revealed a novel mechanism of M1 microglia/macrophages swarming at lesion sites at the acute phase following SCI, and provide potential therapeutic approaches for neuroinflammation by targeting the astrocytic ET-1 system.
Insights
Spinal cord injury triggers astrocytic endothelin-1 (ET-1) system activation, promoting harmful M1 microglia polarization. Targeting this ET-1 system with inhibitors improves locomotor function recovery in rats.
Area of Science:
- Neuroscience
- Immunology
- Regenerative Medicine
Background:
- Microglia/macrophages adopt a pro-inflammatory M1 phenotype post-spinal cord injury (SCI), exacerbating tissue damage.
- This M1 polarization is a critical factor influencing functional outcomes after SCI.
Purpose of the Study:
- To elucidate the role of the astrocytic endothelin-1 (ET-1) system in microglia polarization following SCI.
- To identify the upstream activators and downstream signaling pathways involved in astrocytic ET-1 system activation.
- To evaluate the therapeutic potential of targeting the astrocytic ET-1 system for SCI recovery.
Main Methods:
- Investigated the activation of the astrocytic ET-1 system immediately after SCI in a rat model.
- Utilized pharmacological inhibitors for protease-activated receptor-1 (PAR-1) and ET-1.
- Assessed microglia phenotype (M1/M2), ET-1 plasma levels, and locomotor function recovery.
Main Results:
- Astrocytic ET-1 system activation drives M1 microglia polarization and suppresses M2 phenotype via YAP activation.
- SCI-induced thrombin activates the astrocytic ET-1 system through PAR-1 signaling pathways.
- Inhibition of PAR-1 and ET-1 effectively reversed M1 microglia phenotype and improved locomotor function in rats.
Conclusions:
- A novel mechanism involving the astrocytic ET-1 system in M1 microglia/macrophage accumulation post-SCI was uncovered.
- The astrocytic ET-1 system, activated by thrombin, represents a potential therapeutic target for neuroinflammation and functional recovery after SCI.
