title: Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia.
abstract: Results of recent studies reveal vascular and neuroprotective effects of matrix metalloproteinase-9 (MMP-9) inhibition and MMP-9 gene deletion in experimental stroke. However, the cellular source of MMP-9 produced in the ischemic brain and the mechanistic basis of MMP-9-mediated brain injury require elucidation. In the present study, we used MMP-9-/- mice and chimeric knockouts lacking either MMP-9 in leukocytes or in resident brain cells to test the hypothesis that MMP-9 released from leukocytes recruited to the brain during postischemic reperfusion contributes to this injury phenotype. We also tested the hypothesis that MMP-9 promotes leukocyte recruitment to the ischemic brain and thus is proinflammatory. The extent of blood-brain barrier (BBB) breakdown, the neurological deficit, and the volume of infarction resulting from transient focal stroke were abrogated to a similar extent in MMP-9-/- mice and in chimeras lacking leukocytic MMP-9 but not in chimeras with MMP-9-containing leukocytes. Zymography and Western blot analysis from these chimeras confirmed that the elevated MMP-9 expression in the brain at 24 h of reperfusion is derived largely from leukocytes. MMP-9-/- mice exhibited a reduction in leukocyte-endothelial adherence and a reduction in the number of neutrophils plugging capillaries and infiltrating the ischemic brain during reperfusion; microvessel immunopositivity for collagen IV was also preserved in these animals. These latter results document proinflammatory actions of MMP-9 in the ischemic brain. Overall, our findings implicate leukocytes, most likely neutrophils, as a key cellular source of MMP-9, which, in turn, promotes leukocyte recruitment, causes BBB breakdown secondary to microvascular basal lamina proteolysis, and ultimately contributes to neuronal injury after transient focal stroke.
authors.affiliation: Dept. of Neurosurgery, Washington Univ. School of Medicine, 660 S. Euclid Ave., Box 8057, St. Louis, MO 63110, USA. gidday@nsurg.wustl.edu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gidday
authors.forename: Yvan G
authors.initials: YG
authors.lastname: Gasche
authors.forename: Jean-C
authors.initials: JC
authors.lastname: Copin
authors.forename: Aarti R
authors.initials: AR
authors.lastname: Shah
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Perez
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
authors.forename: T S
authors.initials: TS
authors.lastname: Park
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001808:Blood Vessels / Q000473:pathology; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D002448:Cell Adhesion; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D024141:Collagen Type IV / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D006439:Hemodynamics; D018836:Inflammation Mediators / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000517:prevention & control; D020556:Neutrophil Infiltration
chemical_list: D024141:Collagen Type IV; D018836:Inflammation Mediators; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9