Ong, CWM; Fox, K; Ettorre, A; Elkington, PT; Friedland, JS
(2018)
Hypoxia increases neutrophil-driven matrix destruction after exposure to Mycobacterium tuberculosis.
Sci Rep, 8 (1).
p. 11475.
ISSN 2045-2322
https://doi.org/10.1038/s41598-018-29659-1
SGUL Authors: Friedland, Jonathan Samuel
Abstract
The importance of neutrophils in the pathology of tuberculosis (TB) has been recently established. We demonstrated that TB lesions in man are hypoxic, but how neutrophils in hypoxia influence lung tissue damage is unknown. We investigated the effect of hypoxia on neutrophil-derived enzymes and tissue destruction in TB. Human neutrophils were stimulated with M. tuberculosis (M.tb) or conditioned media from M.tb-infected monocytes (CoMTB). Neutrophil matrix metalloproteinase-8/-9 and elastase secretion were analysed by luminex array and gelatin zymography, gene expression by qPCR and cell viability by flow cytometry. Matrix destruction was investigated by confocal microscopy and functional assays and neutrophil extracellular traps (NETs) by fluorescence assay. In hypoxia, neutrophil MMP-8 secretion and gene expression were up-regulated by CoMTB. MMP-9 activity and neutrophil elastase (NE) secretion were also increased in hypoxia. Hypoxia inhibited NET formation and both neutrophil apoptosis and necrosis after direct stimulation by M.tb. Hypoxia increased TB-dependent neutrophil-mediated matrix destruction of Type I collagen, gelatin and elastin, the main structural proteins of the human lung. Dimethyloxalylglycin (DMOG), which stabilizes hypoxia-inducible factor-1α, increased neutrophil MMP-8 and -9 secretion. Hypoxia in our cellular model of TB up-regulated pathways that increase neutrophil secretion of MMPs that are implicated in matrix destruction.
Item Type: |
Article
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Additional Information: |
Open Access
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
© The Author(s) 2018 |
Keywords: |
Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, EXTRACELLULAR TRAPS, INNATE IMMUNITY, METALLOPROTEINASES, INFLAMMATION, HIF-1-ALPHA, ACTIVATION, GROWTH, BRONCHIECTASIS, CONTRIBUTES, EXPRESSION |
Journal or Publication Title: |
Sci Rep |
ISSN: |
2045-2322 |
Language: |
eng |
Dates: |
Date | Event |
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31 July 2018 | Published | 11 July 2018 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
30065292 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/110267 |
Publisher's version: |
https://doi.org/10.1038/s41598-018-29659-1 |
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