Role of polymorphonuclear neutrophils in the reperfused ischemic brain: insights from cell-type-specific
Dirk M Hermann1, Christoph Kleinschnitz2, Matthias Gunzer3
1Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, Essen D-45122, Germany.
Abstract:
Polymorphonuclear neutrophil granulocytes (PMNs) are part of the early post-ischemic immune response that orchestrates the removal of infarcted brain tissue. PMNs contribute to secondary brain injury in experimental stroke models. In human patients, high PMN-to-lymphocyte ratios in peripheral blood are predictive of poor stroke outcome. Following earlier studies indicating that the cerebral microvasculature forms an efficient barrier that impedes PMN brain entry even under conditions of ischemia, more recent studies combining intravital two-photon microscopy and ex vivo immunohistochemistry unequivocally demonstrated the accumulation of PMNs in the ischemic brain parenchyma. In the meantime, transgenic mouse lines, such as mice expressing Cre-recombinase and the red fluorescent reporter protein tdTomato under the highly granulocyte-specific locus for the gene Ly6G (so-called Catchup mice), have become available that allow study of dynamic interactions of PMNs with brain parenchymal cells. These mice will further help us understand how PMNs promote brain injury and disturb brain remodeling and plasticity.
Insights
Polymorphonuclear neutrophils (PMNs) infiltrate the brain after stroke, contributing to injury. New mouse models allow detailed study of PMN interactions in the ischemic brain, aiding understanding of stroke pathology.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Polymorphonuclear neutrophils (PMNs) are key in early post-ischemic immune responses, clearing infarcted brain tissue.
- High PMN-to-lymphocyte ratios in peripheral blood correlate with poor stroke outcomes in humans.
- While previously thought to be impeded by the blood-brain barrier, PMNs are now known to accumulate in the ischemic brain parenchyma.
Purpose of the Study:
- To investigate the role of PMNs in secondary brain injury following stroke.
- To understand how PMNs influence brain remodeling and plasticity after ischemic events.
- To leverage new transgenic mouse models for studying dynamic PMN-brain interactions.
Main Methods:
- Utilizing intravital two-photon microscopy to observe PMN behavior in real-time.
- Employing ex vivo immunohistochemistry for detailed analysis of PMN infiltration.
- Employing novel transgenic mouse lines (Catchup mice) for specific PMN labeling and tracking.
Main Results:
- PMNs accumulate within the ischemic brain parenchyma, challenging earlier assumptions about the blood-brain barrier's efficacy.
- Experimental stroke models show PMNs contribute to secondary brain injury.
- High peripheral PMN-to-lymphocyte ratios predict poor stroke outcomes in human patients.
Conclusions:
- PMNs play a significant role in both the acute and chronic phases of stroke pathology.
- Advanced imaging and genetic tools are crucial for dissecting PMN functions in the ischemic brain.
- Further research with these models will elucidate PMN mechanisms in brain injury and recovery.
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