Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.ppat.1004917
Title: Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis
Authors: Ong C.W.M. 
Elkington P.T.
Brilha S.
Ugarte-Gil C.
Tome-Esteban M.T.
Tezera L.B.
Pabisiak P.J.
Moores R.C.
Sathyamoorthy T.
Patel V.
Gilman R.H.
Porter J.C.
Friedland J.S.
Keywords: collagen type 1
gelatin
gelatinase B
hydroxymethylglutaryl coenzyme A reductase kinase
myeloperoxidase
neutrophil collagenase
neutrophil gelatinase associated lipocalin
phosphotransferase
tissue inhibitor of metalloproteinase 1
tissue inhibitor of metalloproteinase 2
enzyme inhibitor
hydroxymethylglutaryl coenzyme A reductase kinase
immunoglobulin enhancer binding protein
MMP8 protein, human
neutrophil collagenase
scleroprotein
adult
anatomical concepts
Article
cell culture
cell stimulation
controlled study
disease severity
enzyme linked immunosorbent assay
extracellular trap
flow cytometry
human
human tissue
immunoblotting
immunofluorescence microscopy
immunohistochemistry
immunopathology
lung biopsy
lung tuberculosis
major clinical study
matrix destruction
neutrophil
protein degradation
protein expression
real time polymerase chain reaction
upregulation
active transport
chemistry
cohort analysis
drug effects
enzymology
host pathogen interaction
immunology
innate immunity
lung
metabolism
Mycobacterium tuberculosis
neutrophil
neutrophil chemotaxis
pathology
phosphorylation
physiology
protein processing
respiratory mucosa
secretion (process)
sputum
Tuberculosis, Pulmonary
Mycobacterium tuberculosis
Active Transport, Cell Nucleus
Adult
AMP-Activated Protein Kinases
Cells, Cultured
Cohort Studies
Enzyme Inhibitors
Extracellular Matrix Proteins
Host-Pathogen Interactions
Humans
Immunity, Innate
Lung
Matrix Metalloproteinase 8
Mycobacterium tuberculosis
Neutrophil Infiltration
Neutrophils
NF-kappa B
Phosphorylation
Protein Processing, Post-Translational
Proteolysis
Respiratory Mucosa
Sputum
Tuberculosis, Pulmonary
Issue Date: 2015
Citation: Ong C.W.M., Elkington P.T., Brilha S., Ugarte-Gil C., Tome-Esteban M.T., Tezera L.B., Pabisiak P.J., Moores R.C., Sathyamoorthy T., Patel V., Gilman R.H., Porter J.C., Friedland J.S. (2015). Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathogens 11 (5) : e1004917. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.ppat.1004917
Rights: Attribution 4.0 International
Abstract: Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease. ? 2015 Ong et al.
Source Title: PLoS Pathogens
URI: https://scholarbank.nus.edu.sg/handle/10635/161936
ISSN: 15537366
DOI: 10.1371/journal.ppat.1004917
Rights: Attribution 4.0 International
Appears in Collections:Elements
Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_1371_journal_ppat_1004917.pdf11.49 MBAdobe PDF

OPEN

NoneView/Download

SCOPUSTM   
Citations

113
checked on May 13, 2022

WEB OF SCIENCETM
Citations

93
checked on Oct 6, 2021

Page view(s)

221
checked on May 12, 2022

Download(s)

1
checked on May 12, 2022

Google ScholarTM

Check

Altmetric


This item is licensed under a Creative Commons License Creative Commons