Please use this identifier to cite or link to this item: https://doi.org/10.1186/s12974-017-0801-1
Title: Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
Authors: Ong, C.W.M 
Pabisiak, P.J
Brilha, S
Singh, P
Roncaroli, F
Elkington, P.T
Friedland, J.S
Keywords: collagen type 4
dexamethasone
gelatinase B
immunoglobulin enhancer binding protein
leukocyte elastase
mitogen activated protein kinase
mitogen activated protein kinase p38
neutrophil collagenase
phosphatidylinositol 3 kinase
protein kinase B
protein S 100
tumor necrosis factor
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
antibody
chromone derivative
collagen type 4
enzyme inhibitor
gelatinase B
immunoglobulin enhancer binding protein
morpholine derivative
oncoprotein
peroxidase
Article
bacterium culture
basement membrane
blood brain barrier
brain biopsy
cell viability
central nervous system tuberculosis
collagen degradation
confocal microscopy
controlled study
enzyme linked immunosorbent assay
fluorescence activated cell sorting
gene expression
genotype
histopathology
human
human experiment
immunofluorescence microscopy
immunohistochemistry
immunopathology
macrophage
monocyte
Mycobacterium tuberculosis
neutrophil
neutrophil count
normal human
protein secretion
real time polymerase chain reaction
signal transduction
supernatant
upregulation
cell culture
central nervous system tuberculosis
dose response
drug effects
female
gene expression regulation
genetics
immunology
leukocyte
male
metabolism
neutrophil
pathology
physiology
secretion (process)
Antibodies
Cells, Cultured
Chromones
Collagen Type IV
Dose-Response Relationship, Drug
Enzyme Inhibitors
Female
Gene Expression Regulation, Bacterial
Humans
Leukocytes
Male
Matrix Metalloproteinase 9
Morpholines
Mycobacterium tuberculosis
Neutrophils
NF-kappa B
Oncogene Protein v-akt
Peroxidase
Signal Transduction
Tuberculosis, Central Nervous System
Up-Regulation
Issue Date: 2017
Citation: Ong, C.W.M, Pabisiak, P.J, Brilha, S, Singh, P, Roncaroli, F, Elkington, P.T, Friedland, J.S (2017). Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis. Journal of Neuroinflammation 14 (1) : 31. ScholarBank@NUS Repository. https://doi.org/10.1186/s12974-017-0801-1
Rights: Attribution 4.0 International
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. © 2017 The Author(s).
Source Title: Journal of Neuroinflammation
URI: https://scholarbank.nus.edu.sg/handle/10635/179530
ISSN: 17422094
DOI: 10.1186/s12974-017-0801-1
Rights: Attribution 4.0 International
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