Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-16250-3
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dc.titleMatrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis
dc.contributor.authorBrilha, S
dc.contributor.authorOng, C.W.M
dc.contributor.authorWeksler, B
dc.contributor.authorRomero, N
dc.contributor.authorCouraud, P.-O
dc.contributor.authorFriedland, J.S
dc.date.accessioned2020-10-20T10:18:35Z
dc.date.available2020-10-20T10:18:35Z
dc.date.issued2017
dc.identifier.citationBrilha, S, Ong, C.W.M, Weksler, B, Romero, N, Couraud, P.-O, Friedland, J.S (2017). Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis. Scientific Reports 7 (1) : 16031. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-16250-3
dc.identifier.issn2045-2322
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/178557
dc.description.abstractCentral nervous system tuberculosis (CNS TB) has a high mortality and morbidity associated with severe inflammation. The blood-brain barrier (BBB) protects the brain from inflammation but the mechanisms causing BBB damage in CNS TB are uncharacterized. We demonstrate that Mycobacterium tuberculosis (Mtb) causes breakdown of type IV collagen and decreases tight junction protein (TJP) expression in a co-culture model of the BBB. This increases permeability, surface expression of endothelial adhesion molecules and leukocyte transmigration. TJP breakdown was driven by Mtb-dependent secretion of matrix metalloproteinase (MMP)-9. TJP expression is regulated by Sonic hedgehog (Shh) through transcription factor Gli-1. In our model, the hedgehog pathway was downregulated by Mtb-stimulation, but Shh levels in astrocytes were unchanged. However, Scube2, a glycoprotein regulating astrocyte Shh release was decreased, inhibiting Shh delivery to brain endothelial cells. Activation of the hedgehog pathway by addition of a Smoothened agonist or by addition of exogenous Shh, or neutralizing MMP-9 activity, decreased permeability and increased TJP expression in the Mtb-stimulated BBB co-cultures. In summary, the BBB is disrupted by downregulation of the Shh pathway and breakdown of TJPs, secondary to increased MMP-9 activity which suggests that these pathways are potential novel targets for host directed therapy in CNS TB. © 2017 The Author(s).
dc.publisherNature Publishing Group
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20201031
dc.subjectgelatinase B
dc.subjectsonic hedgehog protein
dc.subjectblood brain barrier
dc.subjectcell culture
dc.subjectcell line
dc.subjectcentral nervous system tuberculosis
dc.subjectconditioned medium
dc.subjectenzyme linked immunosorbent assay
dc.subjectgenetics
dc.subjecthuman
dc.subjectmetabolism
dc.subjectMycobacterium tuberculosis
dc.subjectpathogenicity
dc.subjectphysiology
dc.subjectsignal transduction
dc.subjecttight junction
dc.subjectBlood-Brain Barrier
dc.subjectCell Line
dc.subjectCells, Cultured
dc.subjectCulture Media, Conditioned
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectHedgehog Proteins
dc.subjectHumans
dc.subjectMatrix Metalloproteinase 9
dc.subjectMycobacterium tuberculosis
dc.subjectSignal Transduction
dc.subjectTight Junctions
dc.subjectTuberculosis, Central Nervous System
dc.typeArticle
dc.contributor.departmentDEPT OF MEDICINE
dc.description.doi10.1038/s41598-017-16250-3
dc.description.sourcetitleScientific Reports
dc.description.volume7
dc.description.issue1
dc.description.page16031
dc.published.statepublished
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