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Such biased polarization shapes the functional outcomes by expanding tissue damage. In the present study, the astrocytic endothelin\u20101 (ET\u20101) 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<jats:sub>A<\/jats:sub> and ET<jats:sub>B<\/jats:sub> receptors. In addition, the activation of astrocytic ET\u20101 system results in elevation of blood plasma ET\u20101 level, suggesting a high diagnostic value. SCI\u2010induced thrombin is pinpointed as a crucial activator of the astrocytic ET\u20101 system. The serine protease dramatically promotes the astrocytic expression of preproendothelin\u20101 (ppET\u20101) through protease\u2010activated receptor\u20101 (PAR\u20101)\/RhoA\/NF\u2010\u03baB and PAR\u20101\/MAPKs\/NF\u2010\u03baB signal pathways. Meanwhile, it induces the expression of astrocytic endothelin\u2010converting enzyme 1 (ECE\u20101) responsible for mature ET\u20101 processing. Pharmacological inhibitors of PAR\u20101 and ET\u20101 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\u20101 system.<\/jats:p>","DOI":"10.1002\/advs.202507215","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T03:48:38Z","timestamp":1748576918000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Astrocytic ET\u20101 System Determines Microglia Phenotype Following Spinal Cord Injury"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3108-7890","authenticated-orcid":false,"given":"Bingqiang","family":"He","sequence":"first","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co\u2010innovation Center of Neuroregeneration Nantong University  19 Qixiu Road Nantong 226001 P.R. 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