Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury
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 en...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202507215 |
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| author | Bingqiang He Si Xu Mengdi Li Hui Li Shaolan Li Li Niu Honghua Song Rixin Cai Yue Zhou Zhilong Cao Yingjie Wang Yongjun Wang |
| author_facet | Bingqiang He Si Xu Mengdi Li Hui Li Shaolan Li Li Niu Honghua Song Rixin Cai Yue Zhou Zhilong Cao Yingjie Wang Yongjun Wang |
| author_sort | Bingqiang He |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-63fbfa5a61534468a6f09f904fc78fe2 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-63fbfa5a61534468a6f09f904fc78fe22025-08-23T14:12:08ZengWileyAdvanced Science2198-38442025-08-011231n/an/a10.1002/advs.202507215Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord InjuryBingqiang He0Si Xu1Mengdi Li2Hui Li3Shaolan Li4Li Niu5Honghua Song6Rixin Cai7Yue Zhou8Zhilong Cao9Yingjie Wang10Yongjun Wang11Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaKey Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co‐innovation Center of Neuroregeneration Nantong University 19 Qixiu Road Nantong 226001 P.R. ChinaAbstract 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.https://doi.org/10.1002/advs.202507215thrombinendothelin‐1astrocytesmicrogliaphenotype |
| spellingShingle | Bingqiang He Si Xu Mengdi Li Hui Li Shaolan Li Li Niu Honghua Song Rixin Cai Yue Zhou Zhilong Cao Yingjie Wang Yongjun Wang Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury Advanced Science thrombin endothelin‐1 astrocytes microglia phenotype |
| title | Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury |
| title_full | Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury |
| title_fullStr | Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury |
| title_full_unstemmed | Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury |
| title_short | Astrocytic ET‐1 System Determines Microglia Phenotype Following Spinal Cord Injury |
| title_sort | astrocytic et 1 system determines microglia phenotype following spinal cord injury |
| topic | thrombin endothelin‐1 astrocytes microglia phenotype |
| url | https://doi.org/10.1002/advs.202507215 |
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