中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (5): 1033-1039.doi: 10.4103/1673-5374.355759

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

阻断PSD-93-CX3CL1的相互作用促进急性缺血性脑卒中后小胶质细胞的表型转化

  

  • 出版日期:2023-05-15 发布日期:2022-11-01
  • 基金资助:
    江苏省自然科学基金会

Blocking postsynaptic density-93 binding to C‑X3‑C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke

Xiao-Wei Cao1, 2, 3, 4, 5, 6, 7, #, Hui Yang8, 9, #, Xiao-Mei Liu10, Shi-Ying Lou1, 2, 11, Li-Ping Kong11, Liang-Qun Rong11, Jun-Jun Shan11, Yun Xu1, 2, 3, 4, 5, 6, Qing-Xiu Zhang1, 2, 3, 4, 5, 6, *#br#   

  1. 1Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China; 2Nanjing Drum Tower Clinical College of Xuzhou Medical University, Nanjing, Jiangsu Province, China;  3Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu Province, China;  4Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu Province, China; 5Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu Province, China;  6Nanjing Neurology Clinic Medical Center, Nanjing, Jiangsu Province, China;  7Department of Neurology, Lianyungang Municipal Hospital, Affiliated Hospital of Xuzhou Medical University, Lianyungang, Jiangsu Province, China;  8Department of Neurosurgery of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu Province, China;  9Department of Neurosurgery, Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  10Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity, Xuzhou Medical University, Xuzhou, Jiangsu Province, China;  11Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China
  • Online:2023-05-15 Published:2022-11-01
  • Contact: Qing-Xiu Zhang, MD, zhangqingxiu@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82071304 (to QXZ), 81671149 (to QXZ), and 81971179 (to XML), the Natural Science Foundation of Jiangsu Province, Nos. BK20191463 (to XML) and BK20161167 (to QXZ). 

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摘要：

作者既往研究表明，兴奋性突触后蛋白(PSD-93)通过与CX3CL1的357-395aa氨基酸序列相互作用来介导小胶质细胞和神经元之间的串扰，并诱导小胶质细胞极化。更重要的是，干扰神经元兴奋性突触后蛋白（PSD-93）与神经元特异表达的趋化因子CX3CL1的结合的多肽Tat-CX3CL1（357-395aa）改善了急性缺血性脑卒中后的神经功能，但其潜在机制仍不清楚。此次实验首先观察了小鼠大脑中动脉阻塞再灌注不同时间点M1和M2型小胶质细胞特异性细胞因子或趋化因子的表达变化趋势，发现促炎表型M1在脑卒中后6 h增加，灌注后24 h达到峰值，而M2表型在再灌注后6h和24 h下降；融合小肽Tat-CX3CL1 (357-395aa)通过减少可溶性CX3CL1的产生，促进了小胶质细胞从M1型向M2型极化；应用整合素和金属蛋白酶结构域17抑制剂GW280264x可以通过减少可溶性CX3CL1的形成来抑制小胶质细胞从M1向M2的极化。最后，Tat-CX3CL1 (357-395aa)还可通过改善脑白质完整性，减轻脑卒中后认知功能障碍。因此，Tat-CX3CL1 (357-395aa)通过促进M1向M2的小胶质细胞极化转化，促进缺血性脑卒中后功能恢复，可能是一种潜在的缺血性脑卒中治疗药物。

https://orcid.org/0000-0001-5285-2908 (Qing-Xiu Zhang)

Abstract: We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C‑X3‑C motif chemokine ligand 1 (CX3CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3CL1 (comprising amino acids 357–395 of CX3CL1) disrupts the interaction between postsynaptic density-93 and CX3CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3CL1 (357–395aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3CL1. Furthermore, the a disintegrin and metalloprotease domain 17 (ADAM17) inhibitor GW280264x, which inhibits metalloprotease activity and prevents CX3CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3CL1 formation. Additionally, Tat-CX3CL1 (357–395aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3CL1 (357–395aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3CL1 (357–395aa) is a potential therapeutic agent for ischemic stroke.  

Key words: a disintegrin and metalloprotease domain 17, cerebral ischemia/reperfusion, C?X3?C motif chemokine ligand 1, GW280264x, microglia, neuroinflammation, postsynaptic density-93, Tat-CX3CL1 (357–395aa)