Cao Chang, Liu Ting, Peng Lu, Li Lianxin, Xu Zhongmou, Li Xiang, Chen Gang, Li Haiying, Bai Lei
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
Institute of Stroke Research, Soochow University, Suzhou, 215006, China.
Mol Brain. 2025 May 21;18(1):46. doi: 10.1186/s13041-025-01197-8.
Ischemic stroke remains a leading cause of mortality and long-term disability, with reperfusion injury contributing significantly to poor clinical outcomes. Microglia, the primary immune cells of the central nervous system, play a dual role in ischemic stroke by both exacerbating injury through neuroinflammation and supporting recovery through neuroprotection. This study aimed to explore the role of CD74, a gene upregulated in microglia following ischemia-reperfusion injury. Using single-cell RNA sequencing and bulk RNA sequencing, we identified CD74 as a potential target involved in microglial-mediated neuroinflammation. We observed a significant increase in CD74 expression in microglia following middle cerebral artery occlusion/reperfusion (MCAO/R), which correlated with pro-inflammatory cytokine production and neuroinflammation. Targeted knockdown of CD74 in microglia using CX3CR1Cre/ERT2 mice led to a reduction in infarct volume, inflammatory cytokine levels, and long-term neurological deficits. Behavioral tests showed improved motor coordination, sensory function, and exploratory behavior in CD74 knockdown mice. These results suggest that CD74 is a critical mediator of microglia-driven neuroinflammation, and targeting CD74 may represent a promising therapeutic strategy for reducing ischemic brain injury and promoting recovery after stroke.
缺血性中风仍然是导致死亡和长期残疾的主要原因，再灌注损伤对不良临床结果有显著影响。小胶质细胞是中枢神经系统的主要免疫细胞，在缺血性中风中发挥双重作用，既通过神经炎症加剧损伤，又通过神经保护支持恢复。本研究旨在探讨CD74的作用，CD74是一种在缺血再灌注损伤后小胶质细胞中上调的基因。通过单细胞RNA测序和批量RNA测序，我们确定CD74是参与小胶质细胞介导的神经炎症的潜在靶点。我们观察到大脑中动脉闭塞/再灌注（MCAO/R）后小胶质细胞中CD74表达显著增加，这与促炎细胞因子产生和神经炎症相关。使用CX3CR1Cre/ERT2小鼠对小胶质细胞中的CD74进行靶向敲低导致梗死体积、炎症细胞因子水平和长期神经功能缺损减少。行为测试显示，CD74敲低小鼠的运动协调、感觉功能和探索行为有所改善。这些结果表明，CD74是小胶质细胞驱动的神经炎症的关键介质，靶向CD74可能是减少缺血性脑损伤和促进中风后恢复的一种有前景的治疗策略。
