Shuang Zhang, Mengqi Yuan, Jinchuan Zhou, Zhao Yuan, Liuyongwei Wang, Chang‐Xiong Gong, Hui Lü, Xiaofeng Cheng, Xiaoman Wang, Qian He, Linlin Hu, Bingqiao Wang, Chengkang He, Yiliang Fang, Sen Lin, Wenjie Zi, Ying He, Chenhao Zhao, Hongting Zheng, Jianqin Niu, Feng Mei, Bao‐liang Sun, Qi Xie, Qingwu Yang
Following central nervous system injury, astrocytes form borders that were traditionally regarded as physical barriers. Emerging evidence demonstrates their capacity to regulate inflammation and repair; however, the specific characteristics of these border astrocytes and their interactions with immune cells remain insufficiently characterized. Using single-cell sequencing and spatial transcriptomics, we identified astrocytes expressing the interferon-inducible protein bone marrow stromal cell antigen 2 (BST2) enriched at injury boundaries that promote microglial recruitment via C3/C3aR signaling. Astrocyte-specific Bst2 knockout reduced astrocyte-microglia interactions and attenuated border formation, correlating with early neurological improvement after stroke. Mechanistically, BST2 enhanced C3 expression through protein kinase C-βII (PKCβII) phosphorylation. Moreover, treatment with a BST2 monoclonal antibody diminished astrocyte-microglia interactions and improved neurological function. Together, these findings highlight the pivotal role of astrocyte-microglia interactions in lesion border formation and suggest that BST2 may represent a therapeutic target to modulate these interactions and reduce early brain injury after stroke.