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

Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
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.
1742-2094
1-12
Ong, Catherine W.M.
6b40e697-1305-4f92-a8cb-7f84d7110c96
Pabisiak, Przemyslaw J.
6c4defbb-74b5-4b32-973d-6f41f1b112e9
Brilha, Sara
acd2a966-ffbd-4f38-92b7-9a189d13d668
Singh, Poonam
912ecd81-189c-44cc-ace3-acfd50d1610f
Roncaroli, Frederico
5e9caeae-3129-41d5-8b88-8ab57dfa26bd
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a
Ong, Catherine W.M.
6b40e697-1305-4f92-a8cb-7f84d7110c96
Pabisiak, Przemyslaw J.
6c4defbb-74b5-4b32-973d-6f41f1b112e9
Brilha, Sara
acd2a966-ffbd-4f38-92b7-9a189d13d668
Singh, Poonam
912ecd81-189c-44cc-ace3-acfd50d1610f
Roncaroli, Frederico
5e9caeae-3129-41d5-8b88-8ab57dfa26bd
Elkington, Paul T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a

Ong, Catherine W.M., Pabisiak, Przemyslaw J., Brilha, Sara, Singh, Poonam, Roncaroli, Frederico, Elkington, Paul T. and Friedland, Jon S. (2017) Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis. Journal of Neuroinflammation, 14 (31), 1-12. (doi:10.1186/s12974-017-0801-1).

Record type: 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.

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More information

Accepted/In Press date: 23 January 2017
e-pub ahead of print date: 7 February 2017
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 407628
URI: https://eprints.soton.ac.uk/id/eprint/407628
ISSN: 1742-2094
PURE UUID: e31059b2-c251-4ce0-9055-19dae77cde8e
ORCID for Paul T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

Catalogue record

Date deposited: 16 Apr 2017 17:06
Last modified: 03 Dec 2019 01:38

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