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Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis

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Title: Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
Authors: Ong, C
Pabisiak, P
Dos Santos Brilha, S
Singh, P
Roncaroli, F
Elkington, P
Friedland, J
Item Type: Journal Article
Abstract: Background 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. Methods 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. Results 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. Conclusions 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.
Issue Date: 7-Feb-2017
Date of Acceptance: 7-Feb-2017
URI: http://hdl.handle.net/10044/1/44395
DOI: https://dx.d.doi.org/10.1186/s12974-017-0801-1
ISSN: 1742-2094
Publisher: BioMed Central
Journal / Book Title: Journal of Neuroinflammation
Volume: 14
Copyright Statement: © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Immunopathology
Matrix metalloproteinase
Neutrophils
Tuberculosis
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
1107 Immunology
Publication Status: Published
Article Number: 31
Appears in Collections:Department of Medicine (up to 2019)