Imperial College London
Alternate

ProfessorJonFriedland

Faculty of Medicine, Department of Infectious Disease

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 8521j.friedland Website

 
 
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Assistant

 

Ms Teyanna Gaeta +44 (0)20 3313 1943

 
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Location

 

8N21ACommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ong:2017:10.1186/s12974-017-0801-1,
author = {Ong, C and Pabisiak, P and Dos, Santos Brilha S and Singh, P and Roncaroli, F and Elkington, P and Friedland, J},
doi = {10.1186/s12974-017-0801-1},
journal = {Journal of Neuroinflammation},
title = {Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis},
url = {http://dx.doi.org/10.1186/s12974-017-0801-1},
volume = {14},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundCentral 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.MethodsHuman 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.ResultsMMP-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.ConclusionsMultiple 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.
AU  - Ong,C
AU  - Pabisiak,P
AU  - Dos,Santos Brilha S
AU  - Singh,P
AU  - Roncaroli,F
AU  - Elkington,P
AU  - Friedland,J
DO  - 10.1186/s12974-017-0801-1
PY  - 2017///
SN  - 1742-2094
TI  - Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
T2  - Journal of Neuroinflammation
UR  - http://dx.doi.org/10.1186/s12974-017-0801-1
UR  - http://hdl.handle.net/10044/1/44395
VL  - 14
ER  -
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