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Microglial cell loss after ischemic stroke favors brain neutrophil accumulation

AuthorsOtxoa de Amezaga, Amaia; Miró-Mur, Francesc; Pedragosa, Jordi; Gallizioli, Mattia; Justicia, Carles ; Gaja-Capdevila, Núria; Ruíz-Jaen, Francisca; Salas-Perdomo, Angélica ; Bosch, Anna; Calvo, María; Márquez-Kisinousky, Leonardo ; Denes, Adam; Gunzer, Matthias; Planas, Anna M.
Brain ischemia
Colony stimulating factor 1 receptor
Issue Date2019
PublisherSpringer Nature
CitationActa Neuropathologica 137: 321-341 (2019)
AbstractStroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood–brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelial basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or a suggested translocation from the skull bone marrow. Based on previous observations of microglia phagocytosing neutrophils recruited to the ischemic brain lesion, we hypothesized that microglial cells might control neutrophil accumulation in the injured brain. We studied a model of permanent occlusion of the middle cerebral artery in mice, including microglia- and neutrophil-reporter mice. Using various in vitro and in vivo strategies to impair microglial function or to eliminate microglia by targeting colony stimulating factor 1 receptor (CSF1R), this study demonstrates that microglial phagocytosis of neutrophils has fundamental consequences for the ischemic tissue. We found that reactive microglia engulf neutrophils at the periphery of the ischemic lesion, whereas local microglial cell loss and dystrophy occurring in the ischemic core are associated with the accumulation of neutrophils first in perivascular spaces and later in the parenchyma. Accordingly, microglia depletion by long-term treatment with a CSF1R inhibitor increased the numbers of neutrophils and enlarged the ischemic lesion. Hence, microglial phagocytic function sets a critical line of defense against the vascular and tissue damaging capacity of neutrophils in brain ischemia.
Publisher version (URL)http://dx.doi.org/10.1007/s00401-018-1954-4
Identifiersdoi: 10.1007/s00401-018-1954-4
e-issn: 1432-0533
issn: 0001-6322
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