Blocking postsynaptic density-93 binding to C-X3-C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke
Xiao-Wei Cao1
Hui Yang2
Xiao-Mei Liu3
Shi-Ying Lou4
Li-Ping Kong5
Liang-Qun Rong5
Jun-Jun Shan5
Yun Xu6
Qing-Xiu Zhang6
1.Department of Neurology of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China;Nanjing Drum Tower Clinical College of Xuzhou Medical University,Nanjing,Jiangsu Province,China;Institute of Brain Sciences,Nanjing University,Nanjing,Jiangsu Province,China;Jiangsu Key Laboratory for Molecular Medicine,Medical School of Nanjing University,Nanjing,Jiangsu Province,China;Jiangsu Province Stroke Center for Diagnosis and Therapy,Nanjing,Jiangsu Province,China;Nanjing Neurology Clinic Medical Center,Nanjing,Jiangsu Province,China;Department of Neurology,Lianyungang Municipal Hospital,Affiliated Hospital of Xuzhou Medical University,Lianyungang,Jiangsu Province,China2.Department of Neurosurgery of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China;Department of Neurosurgery,Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University,Xuzhou,Jiangsu Province,China3.Jiangsu Key Laboratory of Immunity and Metabolism,Department of Pathogen Biology and Immunology and Laboratory of Infection and Immunity,Xuzhou Medical University,Xuzhou,Jiangsu Province,China4.Department of Neurology of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China;Nanjing Drum Tower Clinical College of Xuzhou Medical University,Nanjing,Jiangsu Province,China;Department of Neurology,Second Affiliated Hospital of Xuzhou Medical University,Xuzhou,Jiangsu Province,China5.Department of Neurology,Second Affiliated Hospital of Xuzhou Medical University,Xuzhou,Jiangsu Province,China6.Department of Neurology of Drum Tower Hospital,Medical School and the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing,Jiangsu Province,China;Nanjing Drum Tower Clinical College of Xuzhou Medical University,Nanjing,Jiangsu Province,China;Institute of Brain Sciences,Nanjing University,Nanjing,Jiangsu Province,China;Jiangsu Key Laboratory for Molecular Medicine,Medical School of Nanjing University,Nanjing,Jiangsu Province,China;Jiangsu Province Stroke Center for Diagnosis and Therapy,Nanjing,Jiangsu Province,China;Nanjing Neurology Clinic Medical Center,Nanjing,Jiangsu Province,China
摘要：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.
机标关键词：blockingligandstrokemotifacutebindingchemokinedensity-93
论文发表日期：2023-05-28
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：7( 1033-1039 )
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