Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Tianjin Medical University General Hospital, Tianjin 300052, China.
Advanced Innovation Center for Human Brain Protection, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Beijing 100050, China.
Pharmacol Res. 2023 Oct;196:106912. doi: 10.1016/j.phrs.2023.106912. Epub 2023 Sep 9.
Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.
小胶质细胞是急性脑损伤的最初反应者，并启动神经炎症以引发继发性组织损伤。然而，控制小胶质细胞炎症活性的关键分子开关仍知之甚少。脑出血 (ICH) 是一种破坏性的中风亚型，其在脑实质内形成血肿，并伴有高死亡率。我们使用 ICH 的小鼠模型发现，CD22 的上调主要发生在小胶质细胞中。CD22 抗体阻断导致神经功能缺损、脑损伤和血肿体积减少。这伴随着炎症活性降低、替代激活标志物（CD206 和 IL-10）的表达增加以及 ICH 后小胶质细胞吞噬活性增强。ICH 后 CD22 阻断还导致磷酸化 SYK 和 AKT 的增加。值得注意的是，在接受集落刺激因子 1 受体抑制剂 PLX5622 耗尽小胶质细胞的 ICH 小鼠中，CD22 阻断的益处被消除。此外，在接受 SYK 抑制剂 R406 的 ICH 小鼠中，CD22 阻断的保护作用减弱。总之，我们的研究结果强调了 CD22 作为控制急性脑损伤后小胶质细胞有害作用的关键分子开关，并为改善 ICH 损伤的结果提供了一种新策略。
