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A Method for Generating Pulmonary Neutrophilia Using Aerosolized Lipopolysaccharide
Published on: December 15, 2014
Pneumolysin induces release of matrix metalloproteinase-8 and -9 from human neutrophils
R Cockeran1, T J Mitchell, C Feldman
1Medical Research Council, Unit for Inflammation and Immunity, Dept of Immunology, University of Pretoria, Tshwane Academic Division of the National Health Laboratory Service, Pretoria. rcockera@medic.up.ac.za
Abstract:
The research question addressed in the current study was: does the pneumococcal pore-forming toxin, pneumolysin, mobilise matrix metalloproteinase (MMP) -8 and -9 from isolated human blood neutrophils at sublytic concentrations of 5, 10 and 20 ng.mL(-1)? MMPs were measured in the supernatants of unstimulated neutrophils and of cells exposed to pneumolysin and the chemoattractant N-formyl-L-methionyl-l-leucyl-l-phenylalanine (f-MLP; 0.1 microM), individually and in combination, using ELISA procedures, and alterations in cytosolic Ca(2+) concentrations were monitored using a fura-2 acetoxymethyl ester (fura-2/AM)-based spectrofluorimetric method. Treatment of neutrophils with pneumolysin alone caused dose-related release of both MMPs, whereas f-MLP caused modest increases; the combination of both activators was, however, most effective. Pneumolysin/f-MLP-activated release of the MMPs from the cells was paralleled by increases in cytosolic Ca(2+). Exposure of human neutrophils to pneumolysin is accompanied by mobilisation of MMPs, which is potentiated by f-MLP. If operative in vivo, pneumolysin-mediated release of MMPs from neutrophils and other cell types may contribute to the pathogenesis of severe pneumococcal disease.
Insights
Pneumolysin toxin releases matrix metalloproteinases (MMPs) from human neutrophils. This release, enhanced by f-MLP, may contribute to severe pneumococcal disease pathogenesis.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Pneumolysin is a pore-forming toxin produced by Streptococcus pneumoniae.
- Matrix metalloproteinases (MMPs) are enzymes involved in tissue remodeling and inflammation.
- Neutrophils play a key role in the innate immune response to bacterial infections.
Purpose of the Study:
- To investigate whether pneumolysin mobilizes MMP-8 and MMP-9 from human neutrophils at sublytic concentrations.
- To determine the effect of pneumolysin alone and in combination with the chemoattractant f-MLP on MMP release.
- To examine the role of cytosolic calcium (Ca2+) in pneumolysin-induced MMP mobilization.
Main Methods:
- Isolated human blood neutrophils were exposed to varying concentrations of pneumolysin and f-MLP.
- MMPs in cell supernatants were quantified using ELISA.
- Cytosolic Ca2+ concentrations were monitored using fura-2/AM spectrofluorimetry.
Main Results:
- Pneumolysin alone induced a dose-dependent release of MMP-8 and MMP-9.
- f-MLP caused modest increases in MMP release.
- The combination of pneumolysin and f-MLP resulted in the most significant MMP release, paralleled by increased cytosolic Ca2+.
Conclusions:
- Pneumolysin exposure mobilizes MMPs from human neutrophils.
- This mobilization is potentiated by the chemoattractant f-MLP.
- Pneumolysin-mediated MMP release may contribute to the pathogenesis of severe pneumococcal disease in vivo.
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