脊髓损伤（SCI）目前仍缺乏有效的治疗手段，部分原因在于对SCI后病理机制的认识不够充分。与外周不同，SCI后的固有免疫反应以M1型巨噬/小胶质细胞介导的慢性持续性炎症为特征，但其维持机制尚不清楚。申请人前期研究发现：SCI后星形胶质细胞发生RIPK3/MLKL介导的慢性程序性坏死（necroptosis）；体外坏死的星形胶质细胞可诱导巨噬细胞向M1表型极化；体内敲除RIPK3可减轻SCI后的M1型炎症。据此，我们推测星形胶质细胞的necroptosis是维持SCI后M1型巨噬/小胶质细胞介导的慢性炎症的重要因素之一。本课题拟采用细胞培养、形态学、分子生物学、遗传学及动物行为学等方法，从坏死星形胶质细胞释放损伤相关分子模式（HMGB1及游离线粒体）的角度验证上述假设，阐明星形胶质细胞necroptosis维持SCI后慢性炎症的机制，以期为SCI的修复治疗提供新思路。

There still lacks effective treatment for spinal cord injury (SCI) currently, partially because the mechanism of pathology of SCI is not very clear. Unlike peripheral injury, the innate immune response after SCI is characterized by M1-type macrophages/microglia-mediated chronic inflammation, but the mechanism of its maintenance remains unknown. We have demonstrated that reactive astrocytes die through RIPK3- and MLKL-mediated necroptosis after SCI. We further found that necroptosis of astrocytes polarized macrophages to M1 phenotype in vitro, while knockout of RIPK3 reduced the expression of pro-inflammatory factors after SCI. Therefore, we hypothesize that necroptosis of astrocytes may be involved in maintaining M1-type macrophages/microglia-mediated chronic inflammation after SCI. In this project, we will testify this hypothesis from aspect of damage associated molecular pattern (DAMP) released by necroptotic astrocytes, like HMGB1 and mitochondria, through application of multiple methods, including cell culture, morphology, molecular biology, genetics and animal behavior. The project could reveal the role and mechanism of necroptosis of astrocytes in chronic inflammation after SCI and provide new insights into treatment for SCI.