Neural Regeneration Research ›› 2023, Vol. 18 ›› Issue (5): 1033-1039.doi: 10.4103/1673-5374.355759

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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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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)