Xiong Ye, Li Zhuo Li, Wang Xiao Wan, Li Ting, Cui Mai Yin, Wang Min Min, Fu Yan Qiong, Zheng Yu, Xiang Wei Wei, Wang Yang, Chen Bai Hui
Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
Department of Histology and Embryology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China.
ACS Chem Neurosci. 2025 Aug 6;16(15):2978-2988. doi: 10.1021/acschemneuro.5c00284. Epub 2025 Jul 24.
Activated microglia rapidly migrate to the infarct site, mediate neuroinflammation, and phagocytose cell debris during the acute stage of ischemic stroke; however, the underlying mechanisms remain unclear. In this study, we utilized a cortical photothrombotic ischemic model and found that unc-51-like autophagy activating kinase 1 (ULK1) knockout mice exhibited increased pro-inflammatory microglia, along with upregulated levels of pro-inflammatory mediators. Further studies revealed that ULK1 deletion impaired the phagocytosis of myelin debris by microglia, thereby exacerbating myelin accumulation in the infarct zone and increasing pro-inflammatory phagocytic microglia. Moreover, coimmunoprecipitation results showed that ULK1 bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) in primary microglia. Subsequently, we observed that the protein levels of ULK1 and phosphorylated nuclear factor κ-B (p-NF-κB) were regulated by the administration of the TRAF6 inhibitor C25-140 in ischemic wild-type (WT) mice. Overall, our study suggests that ULK1 regulates microglial activation and neuroinflammation via the TRAF6/NF-κB signaling pathway in ischemic stroke.
在缺血性中风急性期，活化的小胶质细胞迅速迁移至梗死部位，介导神经炎症并吞噬细胞碎片；然而，其潜在机制仍不清楚。在本研究中，我们利用皮质光血栓形成性缺血模型，发现unc-51样自噬激活激酶1（ULK1）基因敲除小鼠表现出促炎性小胶质细胞增多，同时促炎介质水平上调。进一步研究表明，ULK1缺失损害了小胶质细胞对髓鞘碎片的吞噬作用，从而加剧了梗死区的髓鞘积累，并增加了促炎性吞噬性小胶质细胞。此外，免疫共沉淀结果显示，ULK1与原代小胶质细胞中的肿瘤坏死因子受体相关因子6（TRAF6）结合。随后，我们观察到在缺血野生型（WT）小鼠中，给予TRAF6抑制剂C25-140可调节ULK1和磷酸化核因子κB（p-NF-κB）的蛋白水平。总体而言，我们的研究表明，在缺血性中风中，ULK1通过TRAF6/NF-κB信号通路调节小胶质细胞活化和神经炎症。
