Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation

Neurobiol Dis. 2006 Jul;23(1):87-96. doi: 10.1016/j.nbd.2006.02.006. Epub 2006 Apr 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / metabolism
  • Blood-Brain Barrier / immunology
  • Blood-Brain Barrier / pathology*
  • Blotting, Western
  • Brain / immunology*
  • Brain / metabolism
  • Claudin-5
  • Enzyme Activation / physiology
  • Immunohistochemistry
  • Inflammation / immunology*
  • Inflammation / pathology
  • Laminin / metabolism
  • Lipopolysaccharides / adverse effects
  • Matrix Metalloproteinase 3 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Neutrophils / immunology*
  • Occludin
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tight Junctions / metabolism


  • Claudin-5
  • Cldn5 protein, mouse
  • Laminin
  • Lipopolysaccharides
  • Membrane Proteins
  • Occludin
  • Ocln protein, mouse
  • RNA, Messenger
  • laminin A
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 9