Cerebral endothelial expression of Robo1 affects brain infiltration of polymorphonuclear neutrophils during mouse stroke recovery

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DOIResolve DOI: http://doi.org/10.1016/j.nbd.2013.02.014
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TypeArticle
Journal titleNeurobiology of Disease
ISSN0969-9961
Volume54
Pages2431; # of pages: 8
Subjectglucose; oxygen; receptor protein; ROBO1 protein; Slit protein; Slit1 protein; unclassified drug; animal experiment; animal model; animal tissue; article; brain blood vessel; brain cortex; brain ischemia; brain tissue; cell migration; cerebrovascular accident; controlled study; convalescence; endothelium cell; human; human cell; in vitro study; inflammation; middle cerebral artery occlusion; mouse; neutrophil chemotaxis; nonhuman; priority journal; protein expression; reperfusion; sham procedure; umbilical vein endothelial cell; vascular endothelium; Animals; Blotting, Western; Brain; Chemotaxis, Leukocyte; Disease Models, Animal; Endothelial Cells; HEK293 Cells; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neutrophils; Receptors, Immunologic; Stroke; Transfection
AbstractIncreased brain infiltration of polymorphonuclear neutrophils (PMNs) occurs early after stroke and is important in eliciting brain inflammatory response during stroke recovery. In order to understand the molecular mechanism of PMN entry, we investigated the expression and requirement for Slit1, a chemorepulsive guidance cue, and its cognate receptor, Robo1, in a long-term recovery mouse model of cerebral ischemia. The expression levels of Robo1 were significantly decreased bilaterally at 24. h following reperfusion. Robo1 expression levels remained suppressed in the ipsilateral cortex until 28. d post MCAO-reperfusion, while the levels of Robo1 in the contralateral cortex recovered to the level of sham-operated mouse by 7. d reperfusion. Circulating PMNs express high levels of Slit1, but not Robo1. Influx of PMNs into the ischemic core area occurred early (24. h) after cerebral ischemia, when endothelial Robo1 expression was significantly reduced in the ischemic brain, indicating that Robo1 may form a repulsive barrier to PMN entry into the brain parenchyma. Indeed, blocking Slit1 on PMNs in a transwell migration assay in combination with an antibody blocking of Robo1 on human umbilical vein endothelial cells (HUVEC) significantly increased PMN transmigration during oxygen glucose deprivation, an in vitro model of ischemia. Collectively, in the normal brain, the presence of Slit1 on PMNs, and Robo1 on cerebral endothelial cells, generated a repulsive force to prevent the infiltration of PMNs into the brain. During stroke recovery, a transient reduction in Robo1 expression on the cerebral endothelial cells allowed the uncontrolled infiltration of Slit1-expressing PMNs into the brain causing inflammatory reactions. © 2013.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences (IBS-ISB)
Peer reviewedYes
NPARC number21269908
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Record identifier3aaa48e4-57b4-4a3c-8cbc-f096f92a97c2
Record created2013-12-13
Record modified2016-05-09
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