title: Perivascular microglia promote blood vessel disintegration in the ischemic penumbra.
abstract: The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1(+/GFP) mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia became activated in the stroke penumbra and started to expand cellular protrusions towards adjacent blood vessels. All microglia in the penumbra were found associated with blood vessels within 24 h post reperfusion and partially fully engulfed them. In the same time frame blood vessels became permissive for blood serum components. Migration assays in vitro showed that blood serum proteins leaking into the tissue provided molecular cues leading to the recruitment of microglia to blood vessels and to their activation. Subsequently, these perivascular microglia started to eat up endothelial cells by phagocytosis, which caused an activation of the local endothelium and contributed to the disintegration of blood vessels with an eventual break down of the blood brain barrier. Loss-of-microglia-function studies using CX3CR1(GFP/GFP) mice displayed a decrease in stroke size and a reduction in the extravasation of contrast agent into the brain penumbra as measured by MRI. Potentially, medication directed at inhibiting microglia activation within the first day after stroke could stabilize blood vessels in the penumbra, increase blood flow, and serve as a valuable treatment for patients suffering from ischemic stroke.
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University, University Medical Center, Mainz, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Jolivel
authors.forename: Frank
authors.initials: F
authors.lastname: Bicker
authors.forename: Fabien
authors.initials: F
authors.lastname: Binamé
authors.forename: Robert
authors.initials: R
authors.lastname: Ploen
authors.forename: Stefanie
authors.initials: S
authors.lastname: Keller
authors.forename: René
authors.initials: R
authors.lastname: Gollan
authors.forename: Betty
authors.initials: B
authors.lastname: Jurek
authors.forename: Jérôme
authors.initials: J
authors.lastname: Birkenstock
authors.forename: Laura
authors.initials: L
authors.lastname: Poisa-Beiro
authors.forename: Julia
authors.initials: J
authors.lastname: Bruttger
authors.forename: Verena
authors.initials: V
authors.lastname: Opitz
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schäfer
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Mirko H H
authors.initials: MHH
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine; D049452:Green Fluorescent Proteins