Artikel
Challenging the dogma of neutrophil invasion in ischemic stroke
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Veröffentlicht: | 11. September 2012 |
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Gliederung
Text
It is a well accepted dogma that neutrophils invade the CNS parenchyma in early stroke events starting approximately 15 h and ceasing around the 5th day after stroke onset thereby contributing to blood-barrier breakdown and reperfusion injury. In the present study, we aimed to reevaluate the temporo-spatial distribution of neutrophils in 25 well-characterized, early human stroke cases (17 stage I and 8 combined stage I/II cases) by means of histology, immunohistochemical and immunofluorescent stainings since currently more precise methods are available to define cellular subtypes and localisation. In our cohort, a slight accumulation of CD15-positive neutrophils was observed within blood vessels and the perivascular space. However, virtually no granulocytic infiltration of the CNS parenchyma independent from the localization (ischemic center, penumbra or remote normal appearing tissue) was seen. The major part of CD15-positive granulocytes passing the endothelium was still localized inside the parenchymal, collagen IV-positive basement membrane. Interestingly, at all time points the amount of neutrophils in the CNS parenchyma did not exceed CD68-positive MØs or CD3-positive T-cells. A small cellular fraction within the CNS parenchyma histologically appearing as neutrophils could be characterized as cleaved caspase 3-positive cells indicating apoptosis. Our findings in human stroke cases could be corroborated in a murine transient middle cerebral artery occlusion (tMCAO) model with the use of markers for cellular and basement membrane constituents. In the tMCAO model high-resolution confocal microscopy revealed that neutrophils rarely, if ever, gain access to the CNS parenchyma after the ischemic insult. Furthermore, in vitro studies showed that hypoxia alone failed to induce neutrophil migration across the endothelial monolayer under reestablished flow conditions. In conclusion, our findings shed a new light on the potential role of neutrophils in early stroke events and might at least partly explain several disappointing results in clinical trials that tried to target neutrophils to reduce infarct volume.