Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Adv Sci (Weinh). 2024 Sep;11(36):e2403064. doi: 10.1002/advs.202403064. Epub 2024 Aug 1.
Ischemic stroke (IS) is a leading cause of morbidity and mortality globally and triggers a series of reactions leading to primary and secondary brain injuries and permanent neurological deficits. Microglia in the central nervous system play dual roles in neuroprotection and responding to ischemic brain damage. Here, an IS model is employed to determine the involvement of microglia in phagocytosis at excitatory synapses. Additionally, the effects of pharmacological depletion of microglia are investigated on improving neurobehavioral outcomes and mitigating brain injury. RNA sequencing of microglia reveals an increase in phagocytosis-associated pathway activity and gene expression, and C-type lectin domain family 7 member A (Clec7a) is identified as a key regulator of this process. Manipulating microglial Clec7a expression can potentially regulate microglial phagocytosis of synapses, thereby preventing synaptic loss and improving neurobehavioral outcomes after IS. It is further demonstrat that microglial Clec7a interacts with neuronal myeloid differentiation protein 2 (MD2), a key molecule mediating poststroke neurological injury, and propose the novel hypothesis that MD2 is a ligand for microglial Clec7a. These findings suggest that microglial Clec7a plays a critical role in mediating synaptic phagocytosis in a mouse model of IS, suggesting that Clec7a may be a therapeutic target for IS.
缺血性脑卒中（IS）是全球范围内发病率和死亡率的主要原因，它会引发一系列反应，导致原发性和继发性脑损伤以及永久性神经功能缺陷。中枢神经系统中的小胶质细胞在神经保护和对缺血性脑损伤的反应中发挥双重作用。在这里，我们采用 IS 模型来确定小胶质细胞在兴奋性突触吞噬中的作用。此外，还研究了小胶质细胞药理学耗竭对改善神经行为结局和减轻脑损伤的影响。小胶质细胞的 RNA 测序显示吞噬相关途径的活性和基因表达增加，并且 C 型凝集素结构域家族 7 成员 A（Clec7a）被鉴定为该过程的关键调节因子。操纵小胶质细胞的 Clec7a 表达可能会调节小胶质细胞对突触的吞噬作用，从而防止突触丢失并改善 IS 后的神经行为结局。进一步证明小胶质细胞的 Clec7a 与神经元髓样分化蛋白 2（MD2）相互作用，后者是介导中风后神经损伤的关键分子，并提出了 MD2 是小胶质细胞 Clec7a 的配体的新假设。这些发现表明，小胶质细胞的 Clec7a 在介导 IS 小鼠模型中的突触吞噬中发挥关键作用，提示 Clec7a 可能是 IS 的治疗靶点。
