中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (11): 2413-2423.doi: 10.4103/1673-5374.371365

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

缺血性脑卒中后吞噬能力和趋化功能增强的B细胞新表型

  

  • 出版日期:2023-11-15 发布日期:2023-05-04
  • 基金资助:
    国家自然科学基金项目(82001460),浙江省自然科学基金项目(LQ21H250001)

A novel phenotype of B cells associated with enhanced phagocytic capability and chemotactic function after ischemic stroke

Rui Wang1, #, Huaming Li1, #, Chenhan Ling1, #, Xiaotao Zhang1, Jianan Lu1, Weimin Luan1, Jianmin Zhang1, 2, 3, *, Ligen Shi1, 4, *   

  1. 1Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; 2Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang Province, China; 3Stroke Research Center for Diagnostic and Therapeutic Technologies of Zhejiang Province, Hangzhou, Zhejiang Province, China; 4Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, China
  • Online:2023-11-15 Published:2023-05-04
  • Contact: Ligen Shi, MD, PhD, slg0904@zju.edu.cn; Jianmin Zhang, MD, zjm135@zju.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82001460 and the Natural Science Foundation of Zhejiang Province, No. LQ21H250001 (both to LS).

摘要:

越来越多的证据表明B细胞参与了神经炎症和神经再生,然而其在缺血性脑卒中中的作用尚不清楚。此次研究从瞬时大脑中动脉闭塞构建缺血性脑卒中大鼠模型大脑中分离的CD45高浸润免疫细胞中得到一种新型B细胞,即巨噬细胞样B细胞,且以共表达B细胞和巨噬细胞标记物为特征,且具有更强的吞噬和趋化功能,其吞噬相关基因表达上调。GO富集分析也发现吞噬体和溶酶体的形成等吞噬相关基因表达上调。巨噬细胞样B细胞的吞噬活性可通过免疫染色和三维重建得到验证,其在脑缺血后可通过TREM2接触髓鞘碎片,进而对其吞噬和内化。此外,细胞间相互作用分析显示,巨噬细胞样B细胞主要通过CCL通路释放多种趋化因子,招募外周免疫细胞。进一步单细胞转录因子分析发现,巨噬细胞样B细胞可能是由于髓系细胞特异性转录因子CEBP家族上调和/或淋巴系细胞特异性转录因子Pax5下调而诱导形成的。此外,这种独特的B细胞表型也可在创伤性脑损伤、阿尔茨海默病以及胶质母细胞瘤大脑组织中检测到。这一结果为缺血性脑卒中中B细胞的吞噬能力和趋化功能提供了一个新的视角,并可能基于B细胞功能的异质性为调控缺血性脑卒中免疫反应和减少中枢神经系统炎症创造新的治疗靶点。

https://orcid.org/0000-0001-7441-6074 (Ligen Shi); https://orcid.org/0000-0002-3184-1502 (Jianmin Zhang)

关键词: 免疫, 缺血性脑卒中, 免疫浸润, 转录组, B细胞, 吞噬, 趋化, 转录因子, 单细胞RNA测序, 瞬时脑缺血再灌注

Abstract: Accumulating evidence has demonstrated the involvement of B cells in neuroinflammation and neuroregeneration. However, the role of B cells in ischemic stroke remains unclear. In this study, we identified a novel phenotype of macrophage-like B cells in brain-infiltrating immune cells expressing a high level of CD45. Macrophage-like B cells characterized by co-expression of B-cell and macrophage markers, showed stronger phagocytic and chemotactic functions compared with other B cells and showed upregulated expression of phagocytosis‐related genes. Gene Ontology analysis found that the expression of genes associated with phagocytosis, including phagosome- and lysosome-related genes, was upregulated in macrophage-like B cells. The phagocytic activity of macrophage-like B cells was verified by immunostaining and three-dimensional reconstruction, in which TREM2-labeled macrophage-like B cells enwrapped and internalized myelin debris after cerebral ischemia. Cell-cell interaction analysis revealed that macrophage-like B cells released multiple chemokines to recruit peripheral immune cells mainly via CCL pathways. Single-cell RNA sequencing showed that the transdifferentiation to macrophage-like B cells may be induced by specific upregulation of the transcription factor CEBP family to the myeloid lineage and/or by downregulation of the transcription factor Pax5 to the lymphoid lineage. Furthermore, this distinct B cell phenotype was detected in brain tissues from mice or patients with traumatic brain injury, Alzheimer’s disease, and glioblastoma. Overall, these results provide a new perspective on the phagocytic capability and chemotactic function of B cells in the ischemic brain. These cells may serve as an immunotherapeutic target for regulating the immune response of ischemic stroke.

Key words: B cell, chemotaxis, immune infiltration, immunity, ischemic stroke, phagocytosis, single-cell RNA sequencing, transcription factor, transcriptome, transient cerebral ischemia/reperfusion