Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-16250-3
Title: Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis
Authors: Brilha, S
Ong, C.W.M 
Weksler, B
Romero, N
Couraud, P.-O
Friedland, J.S
Keywords: gelatinase B
sonic hedgehog protein
blood brain barrier
cell culture
cell line
central nervous system tuberculosis
conditioned medium
enzyme linked immunosorbent assay
genetics
human
metabolism
Mycobacterium tuberculosis
pathogenicity
physiology
signal transduction
tight junction
Blood-Brain Barrier
Cell Line
Cells, Cultured
Culture Media, Conditioned
Enzyme-Linked Immunosorbent Assay
Hedgehog Proteins
Humans
Matrix Metalloproteinase 9
Mycobacterium tuberculosis
Signal Transduction
Tight Junctions
Tuberculosis, Central Nervous System
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Brilha, 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
Rights: Attribution 4.0 International
Abstract: Central 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).
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/178557
ISSN: 2045-2322
DOI: 10.1038/s41598-017-16250-3
Rights: Attribution 4.0 International
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