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Matrix metalloproteinase-9 in pneumococcal meningitis: activation via an oxidative pathway
Damian N Meli1, Stephan Christen, Stephen L Leib
1Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
Abstract:
In experimental bacterial meningitis, matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) contribute to brain damage. MMP-9 increases in cerebrospinal fluid (CSF) during bacterial meningitis and is associated with the brain damage that is a consequence of the disease. This study assesses the origin of MMP-9 in bacterial meningitis and how ROS modulate its activity. Rat brain-slice cultures and rat polymorphonuclear cells (PMNs) that had been challenged with capsule-deficient heat-inactivated Streptococcus pneumoniae R6 (hiR6) released MMP-9. Coincubation with either catalase, with the myeloperoxidase inhibitor azide, or with the hypochlorous acid scavenger methionine almost completely prevented activation, but not the release, of MMP-9, in supernatants of human PMNs stimulated with hiR6. Thus, in bacterial meningitis, both brain-resident cells and invading PMNs may act as sources of MMP-9, and stimulated PMNs may activate MMP-9 via an ROS-dependent pathway. MMP-9 activation by ROS may represent a target for therapeutic intervention in bacterial meningitis.
Insights
Matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) drive brain damage in bacterial meningitis. This study shows ROS activate MMP-9 via a pathway involving polymorphonuclear cells, suggesting a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Microbiology
Background:
- Bacterial meningitis causes brain damage through matrix metalloproteinases (MMPs) and reactive oxygen species (ROS).
- MMP-9 levels elevate in cerebrospinal fluid (CSF) during meningitis, correlating with brain injury.
Purpose of the Study:
- To investigate the cellular origins of MMP-9 in bacterial meningitis.
- To determine how ROS influence MMP-9 activity.
Main Methods:
- Utilized rat brain-slice cultures and rat polymorphonuclear cells (PMNs) stimulated with heat-inactivated Streptococcus pneumoniae.
- Assessed MMP-9 release and activation in PMN supernatants using catalase, azide, and methionine.
Main Results:
- Both brain-resident cells and invading PMNs released MMP-9 in response to bacterial challenge.
- ROS-dependent pathways, particularly involving myeloperoxidase and hypochlorous acid, were crucial for MMP-9 activation in stimulated human PMNs.
Conclusions:
- Brain-resident cells and PMNs are significant sources of MMP-9 during bacterial meningitis.
- ROS-mediated activation of MMP-9 by PMNs presents a potential therapeutic target for mitigating meningitis-associated brain damage.