Astrocytic ET-1 System Determines Microglia Phenotype Following Spinal Cord Injury

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 ET_A and ET_B 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.