Title |
Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
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Published in |
Journal of Neuroinflammation, February 2017
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DOI | 10.1186/s12974-017-0801-1 |
Pubmed ID | |
Authors |
Catherine W. M. Ong, Przemyslaw J. Pabisiak, Sara Brilha, Poonam Singh, Federico Roncaroli, Paul T. Elkington, Jon S. Friedland |
Abstract |
Central nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined. Human brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors. MMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not. Multiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 63 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 10 | 16% |
Researcher | 9 | 14% |
Student > Bachelor | 8 | 13% |
Student > Master | 7 | 11% |
Student > Postgraduate | 3 | 5% |
Other | 7 | 11% |
Unknown | 19 | 30% |
Readers by discipline | Count | As % |
---|---|---|
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Biochemistry, Genetics and Molecular Biology | 5 | 8% |
Agricultural and Biological Sciences | 5 | 8% |
Immunology and Microbiology | 5 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 4 | 6% |
Other | 7 | 11% |
Unknown | 24 | 38% |