Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation.
Blood-brain barrier (BBB) opening is mediated by matrix metalloproteinases (MMPs) in neuroinflammation. We tested the hypothesis that MMP-3 plays a role in BBB damage, using MMP-3 knockout (KO) mice and lipopolysaccharide (LPS)-induced opening of the BBB. We found less disruption of the BBB after intracerebral LPS injection in MMP-3 KO mice than in wild type (P<0.0006). MMP-3 KO mice had less MMP-9 than WT mice but similar levels of activation. Moreover, MMP-9 mRNA levels were increased to a similar level in both the MMP-3 KO and WT, suggesting both endogenous and exogenous sources. Unbiased stereology showed increased neutrophil counts in the brains of MMP-3 WT compared to KO mice. Degradation of tight junction proteins, claudin-5 and occludin, and the basal lamina protein, laminin-alpha1, was less affected in the KO than in the WT. Our results provide the first in vivo evidence that MMP-3 attacks the basal lamina and tight junction proteins, opening the BBB, thereby facilitating neutrophil influx.
Gurney
Kate J
KJ
Department of Neurology, University of New Mexico Health Sciences Center, MSC10 5620, Albuquerque, NM 87131-0001, USA.
Estrada
Eduardo Y
EY
Rosenberg
Gary A
GA
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology*; D015153:Blotting, Western; D001921:Brain / Q000276:immunology* / Q000378:metabolism; D062507:Claudin-5; D004789:Enzyme Activation / Q000502:physiology; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology*; D062793:Occludin; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism
D062507:Claudin-5; C491511:Cldn5 protein, mouse; D007797:Laminin; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; C084098:laminin A; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9