Clec7a Worsens Long-Term Outcomes after Ischemic Stroke by Aggravating Microglia-Mediated Synapse Elimination

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 br...

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Bibliographic Details
Published in:Advanced science 2024-09, Vol.11 (36), p.e2403064-n/a
Main Authors: Wan, Hanxi, He, Mengfan, Cheng, Chun, Yang, Kexin, Wu, Huanghui, Cong, Peilin, Huang, Xinwei, Zhang, Qian, Shi, Yufei, Hu, Ji, Tian, Li, Xiong, Lize
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Brain research
Clec7a
Disease Models, Animal
Gene expression
Ischemia
ischemic stroke
Ischemic Stroke - metabolism
Kinases
Lectins, C-Type - genetics
Lectins, C-Type - metabolism
Male
Memory
Mice
Mice, Inbred C57BL
microglia
Microglia - metabolism
Neurodegeneration
Phagocytosis
synapses
Synapses - metabolism
Synapses - pathology
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Summary: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.
ISSN:2198-3844
2198-3844
DOI:10.1002/advs.202403064