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Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation
Kate J Gurney1, Eduardo Y Estrada, Gary A Rosenberg
1Department of Neurology, University of New Mexico Health Sciences Center, MSC10 5620, Albuquerque, NM 87131-0001, USA.
Abstract:
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.
Insights
Matrix metalloproteinase-3 (MMP-3) contributes to blood-brain barrier (BBB) damage during neuroinflammation. MMP-3 deficiency protects the BBB by reducing tight junction and basal lamina protein degradation, thereby limiting neutrophil infiltration.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- The blood-brain barrier (BBB) is crucial for central nervous system homeostasis.
- Matrix metalloproteinases (MMPs) are implicated in neuroinflammatory processes and BBB disruption.
- MMP-3's specific role in BBB opening remains unclear.
Purpose of the Study:
- To investigate the role of MMP-3 in lipopolysaccharide (LPS)-induced BBB opening.
- To determine if MMP-3 deficiency protects against BBB damage.
Main Methods:
- Utilized MMP-3 knockout (KO) mice and wild-type (WT) littermates.
- Induced BBB opening via intracerebral lipopolysaccharide (LPS) injection.
- Quantified BBB disruption, neutrophil infiltration, MMP-9 levels, and degradation of tight junction and basal lamina proteins.
Main Results:
- MMP-3 KO mice exhibited significantly less BBB disruption compared to WT mice after LPS injection.
- Neutrophil counts in the brain were lower in MMP-3 KO mice.
- Degradation of tight junction proteins (claudin-5, occludin) and basal lamina protein (laminin-alpha1) was reduced in MMP-3 KO mice.
Conclusions:
- MMP-3 directly contributes to blood-brain barrier opening by degrading key structural proteins.
- MMP-3 facilitates neutrophil infiltration into the brain during neuroinflammation.
- Targeting MMP-3 may offer a therapeutic strategy for neuroinflammatory conditions involving BBB breakdown.
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