Please use this identifier to cite or link to this item: https://doi.org/10.1186/s12974-017-0801-1
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dc.titleComplex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis
dc.contributor.authorOng, C.W.M
dc.contributor.authorPabisiak, P.J
dc.contributor.authorBrilha, S
dc.contributor.authorSingh, P
dc.contributor.authorRoncaroli, F
dc.contributor.authorElkington, P.T
dc.contributor.authorFriedland, J.S
dc.date.accessioned2020-10-23T04:52:52Z
dc.date.available2020-10-23T04:52:52Z
dc.date.issued2017
dc.identifier.citationOng, 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
dc.identifier.issn17422094
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/179530
dc.description.abstractBackground: 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).
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20201031
dc.subjectcollagen type 4
dc.subjectdexamethasone
dc.subjectgelatinase B
dc.subjectimmunoglobulin enhancer binding protein
dc.subjectleukocyte elastase
dc.subjectmitogen activated protein kinase
dc.subjectmitogen activated protein kinase p38
dc.subjectneutrophil collagenase
dc.subjectphosphatidylinositol 3 kinase
dc.subjectprotein kinase B
dc.subjectprotein S 100
dc.subjecttumor necrosis factor
dc.subject2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
dc.subjectantibody
dc.subjectchromone derivative
dc.subjectcollagen type 4
dc.subjectenzyme inhibitor
dc.subjectgelatinase B
dc.subjectimmunoglobulin enhancer binding protein
dc.subjectmorpholine derivative
dc.subjectoncoprotein
dc.subjectperoxidase
dc.subjectArticle
dc.subjectbacterium culture
dc.subjectbasement membrane
dc.subjectblood brain barrier
dc.subjectbrain biopsy
dc.subjectcell viability
dc.subjectcentral nervous system tuberculosis
dc.subjectcollagen degradation
dc.subjectconfocal microscopy
dc.subjectcontrolled study
dc.subjectenzyme linked immunosorbent assay
dc.subjectfluorescence activated cell sorting
dc.subjectgene expression
dc.subjectgenotype
dc.subjecthistopathology
dc.subjecthuman
dc.subjecthuman experiment
dc.subjectimmunofluorescence microscopy
dc.subjectimmunohistochemistry
dc.subjectimmunopathology
dc.subjectmacrophage
dc.subjectmonocyte
dc.subjectMycobacterium tuberculosis
dc.subjectneutrophil
dc.subjectneutrophil count
dc.subjectnormal human
dc.subjectprotein secretion
dc.subjectreal time polymerase chain reaction
dc.subjectsignal transduction
dc.subjectsupernatant
dc.subjectupregulation
dc.subjectcell culture
dc.subjectcentral nervous system tuberculosis
dc.subjectdose response
dc.subjectdrug effects
dc.subjectfemale
dc.subjectgene expression regulation
dc.subjectgenetics
dc.subjectimmunology
dc.subjectleukocyte
dc.subjectmale
dc.subjectmetabolism
dc.subjectneutrophil
dc.subjectpathology
dc.subjectphysiology
dc.subjectsecretion (process)
dc.subjectAntibodies
dc.subjectCells, Cultured
dc.subjectChromones
dc.subjectCollagen Type IV
dc.subjectDose-Response Relationship, Drug
dc.subjectEnzyme Inhibitors
dc.subjectFemale
dc.subjectGene Expression Regulation, Bacterial
dc.subjectHumans
dc.subjectLeukocytes
dc.subjectMale
dc.subjectMatrix Metalloproteinase 9
dc.subjectMorpholines
dc.subjectMycobacterium tuberculosis
dc.subjectNeutrophils
dc.subjectNF-kappa B
dc.subjectOncogene Protein v-akt
dc.subjectPeroxidase
dc.subjectSignal Transduction
dc.subjectTuberculosis, Central Nervous System
dc.subjectUp-Regulation
dc.typeArticle
dc.contributor.departmentDEPT OF MEDICINE
dc.description.doi10.1186/s12974-017-0801-1
dc.description.sourcetitleJournal of Neuroinflammation
dc.description.volume14
dc.description.issue1
dc.description.page31
dc.published.statePublished
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