Zhao Qiang, Li Jiajian, Feng Jingjing, Wang Xin, Liu Yueting, Wang Fei, Liu Liang, Jin Bingxue, Lin Ming, Wang Ya-Chao, Guo Xiuhua, Chen Jieli, Hao Junwei
Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China.
Department of Neurosurgery, The Institute of Translational Medicine, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
Nat Metab. 2025 Sep 23. doi: 10.1038/s42255-025-01379-7.
Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.
慢性神经炎症是中风后恢复的主要障碍，但其潜在机制，尤其是小胶质细胞长期激活与胆固醇代谢之间的联系，尚不完全清楚。在此，我们表明缺血性损伤会诱导小胶质细胞持续激活，从而使慢性炎症持续存在，导致小胶质细胞胆固醇积累和代谢重编程。通过单细胞RNA测序，我们鉴定出了不同的与中风相关的泡沫状小胶质细胞簇，其特征是胆固醇代谢发生广泛重编程。此外，直接向脑内注入游离胆固醇或胆固醇晶体可重现小胶质细胞的持续激活，直接将异常胆固醇代谢与长期神经炎症反应联系起来。在治疗方面，我们证明通过基因或药物激活雄性小鼠体内的CYP46A1来降低小胶质细胞的胆固醇过载，可促进白质修复和功能恢复。这些发现突出了小胶质细胞胆固醇代谢是中风后炎症的关键驱动因素，为针对胆固醇代谢的治疗策略提供了依据，以减轻长期脑损伤并促进神经修复，有可能改善中风相关的残疾结局。
