Li Yan, Fan Qiuyue, Pang Rui, Cai Ling, Qi Jie, Chen Weijie, Zhang Yueman, Chen Chen, Yu Weifeng, Li Peiying
Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Key Laboratory of Anesthesiology, Shanghai Jiao Tong University, Ministry of Education, Shanghai, China.
J Neuroinflammation. 2025 May 27;22(1):143. doi: 10.1186/s12974-025-03465-9.
Peripheral surgery evokes neuroimmune activation in the central nervous system and modulates immune cell polarization in the ischemic brain. However, the phenotypic change of microglia and myeloid cells within post-surgical ischemic brain tissue remain poorly defined. Using an integrated approach that combines single-cell RNA sequencing with comprehensive biological analysis in a perioperative ischemic stroke (PIS) model, we identified a distinct Spp1-positive macrophage/microglia (Spp1 Mac/MG) subgroup that exhibit enriched anti-inflammatory pathways with distinct lipid metabolic reprogrammed profile. Moreover, using immunofluorescence staining, we identified the expression of Glucagon-like peptide-1 receptor (GLP1R) in Spp1F4/80 cells and Spp1Iba-1 cells. Intraperitoneal administration of semaglutide, a GLP1R agonist clinically approved for the treatment of type 2 diabetes mellitus, resulted in a significant reduction of cerebral infarct volume in PIS mice compared to that in ischemic stroke (IS) mice. Meanwhile, semaglutide treatment also increased the proportion of Spp1EduIba-1 cells 3 days after PIS. Using high-parameter flow cytometry, immunofluorescence staining and RNA sequencing, we demonstrated that semaglutide treatment significantly attenuated the expression of neuroinflammatory markers in mice following PIS. We also found that semaglutide treatment significantly ameliorated sensorimotor dysfunction up to 3 days after PIS in mice. Our current finding reveal a novel protective Spp1Mac/MG subset after PIS and demonstrated that it can be upregulated by semaglutide. We propose that targeting Spp1Mac/MG subsets using semaglutide could serve as a promising strategy to attenuate the exacerbated neuroinflammation in PIS.
外周手术可引发中枢神经系统中的神经免疫激活，并调节缺血性脑中免疫细胞的极化。然而，术后缺血性脑组织内小胶质细胞和髓样细胞的表型变化仍不清楚。我们采用一种综合方法，将单细胞RNA测序与围手术期缺血性中风（PIS）模型中的全面生物学分析相结合，鉴定出一个独特的Spp1阳性巨噬细胞/小胶质细胞（Spp1 Mac/MG）亚群，该亚群表现出丰富的抗炎途径以及独特的脂质代谢重编程特征。此外，通过免疫荧光染色，我们在Spp1F4/80细胞和Spp1Iba-1细胞中鉴定出胰高血糖素样肽-1受体（GLP1R）的表达。腹腔注射司美格鲁肽（一种临床上已批准用于治疗2型糖尿病的GLP1R激动剂），与缺血性中风（IS）小鼠相比，PIS小鼠的脑梗死体积显著减小。同时，司美格鲁肽治疗还增加了PIS后3天SppEIduIba-1细胞的比例。通过高参数流式细胞术、免疫荧光染色和RNA测序，我们证明司美格鲁肽治疗显著减弱了PIS后小鼠神经炎症标志物的表达。我们还发现，司美格鲁肽治疗在PIS后长达3天内显著改善了小鼠的感觉运动功能障碍。我们目前的研究结果揭示了PIS后一种新的具有保护作用的Spp1Mac/MG亚群，并证明它可被司美格鲁肽上调。我们提出，使用司美格鲁肽靶向Spp1Mac/MG亚群可能是减轻PIS中加剧的神经炎症的一种有前景的策略。
