Functional Dynamics of Neutrophils After Ischemic Stroke
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Neutrophils are forerunners to brain lesions after ischemic stroke and exert elaborate functions. However, temporal alterations of cell count, polarity, extracellular trap formation, and clearance of neutrophils remain poorly understood. The current study was aimed at providing basic information of neutrophil function throughout a time course following stroke onset in patients and animal subjects. We found that neutrophil constitution in peripheral blood increased soon after stroke onset of patients, and higher neutrophil count indicated detrimental stroke outcomes. Comparably, neutrophil count in peripheral blood of stroke mice peaked at 12 h after cerebral ischemia, followed by a 1-2-day spike in brain lesions. In stroke lesion, clearance of neutrophils peaked at 2 days after stroke and extracellular traps were mostly detected at 2–3 days after stroke. In neutrophil infiltrated into stroke lesion, expression of the N2 marker CD206 was relatively stable. We found that the N2 phenotype facilitated neutrophil clearance by macrophage and did not further induce neuronal death after ischemic injury compared with N0 or N1 neutrophils. Skewing neutrophil toward the N2 phenotype before stroke reduced infarct volumes at 1 day after tMCAO. Conditioned medium of ischemic neurons drove neutrophils away from the protective N2 phenotype and increased the formation of extracellular traps. Conclusively, neutrophil function has an important impact on stroke outcomes. Neutrophil frequency in the peripheral blood could be an early indicator of stroke outcomes. N2 neutrophils facilitate macrophage phagocytosis and are less harmful to ischemic neurons. Directing neutrophils toward the N2 phenotype could be a promising therapeutic approach for ischemic stroke.
KeywordsBrain ischemia Neutrophils Extracellular traps Neuroprotection
Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
W.C. designed and performed the experiments, collected and analyzed data, and drafted the manuscript. S.L. carried out immunostaining, imaging, and quantification and drafted the manuscript. M.H. performed animal experiments and collected data. F.H. and Q.Z. contributed to the experimental design and the manuscript. W.Q. designed the experiment and critically revised the manuscript. X.H. contributed to the experimental design and revised the manuscript. S.G.Z and Z.L. designed and supervised the study and critically revised the manuscript. J.C. edited and revised the MS. All authors read and approved the final manuscript.
This work was supported by the Chinese Natural Science Foundation (NCSF) grants (81671178 to Z. L). Z. L is also supported by the Guangdong Natural Science Foundation grant (2017A030311013).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
All animal experiments were approved by the Third Affiliated Hospital of Sun Yat-sen University and performed following the Guide for the Care and Use of Laboratory Animals and Stroke Treatment. Clinic research was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-sen University.
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