title: Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke.
abstract: Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFβ1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB-431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFβ1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke.
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, California 94158.
authors.forename: David
authors.initials: D
authors.lastname: Fernández-López
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, California 94158.
authors.forename: Joel
authors.initials: J
authors.lastname: Faustino
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, and.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, California 94158.
authors.forename: Nikita
authors.initials: N
authors.lastname: Derugin
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, California 94158.
authors.forename: Elodie
authors.initials: E
authors.lastname: Blanchard
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Simon
authors.affiliation: Institute for Infectious Diseases, University of Bern, 3001 Bern, Switzerland.
authors.forename: Stephen L
authors.identifier: http://orcid.org/0000-0002-1106-6123
authors.initials: SL
authors.lastname: Leib
authors.affiliation: Department of Neurology, University of California-San Francisco, San Francisco, California 94158, Zena.Vexler@ucsf.edu.
authors.forename: Zinaida S
authors.initials: ZS
authors.lastname: Vexler
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D004002:Clodronic Acid / Q000633:toxicity; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D020300:Intracranial Hemorrhages / Q000209:etiology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D050071:Bone Density Conservation Agents; D004149:Dioxoles; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; D004002:Clodronic Acid; D053148:Caspase 3
keywords: TGFβ1; blood–brain barrier; extracellular matrix; inflammation; middle cerebral artery occlusion; postnatal