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Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.

Ong, CW; Elkington, PT; Brilha, S; Ugarte-Gil, C; Tome-Esteban, MT; Tezera, LB; Pabisiak, PJ; Moores, RC; Sathyamoorthy, T; Patel, V; et al. Ong, CW; Elkington, PT; Brilha, S; Ugarte-Gil, C; Tome-Esteban, MT; Tezera, LB; Pabisiak, PJ; Moores, RC; Sathyamoorthy, T; Patel, V; Gilman, RH; Porter, JC; Friedland, JS (2015) Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathogens, 11 (5). ISSN 1553-7374 https://doi.org/10.1371/journal.ppat.1004917
SGUL Authors: Tome, Maria Teresa

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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.

Item Type: Article
Additional Information: © 2015 Ong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: AMP-Activated Protein Kinases, Active Transport, Cell Nucleus, Adult, Cells, Cultured, Cohort Studies, Enzyme Inhibitors, Extracellular Matrix Proteins, Host-Pathogen Interactions, Humans, Immunity, Innate, Lung, Matrix Metalloproteinase 8, Mycobacterium tuberculosis, NF-kappa B, Neutrophil Infiltration, Neutrophils, Phosphorylation, Protein Processing, Post-Translational, Proteolysis, Respiratory Mucosa, Sputum, Tuberculosis, Pulmonary, Lung, Respiratory Mucosa, Neutrophils, Cells, Cultured, Sputum, Humans, Mycobacterium tuberculosis, Tuberculosis, Pulmonary, NF-kappa B, Extracellular Matrix Proteins, Enzyme Inhibitors, Cohort Studies, Neutrophil Infiltration, Protein Processing, Post-Translational, Active Transport, Cell Nucleus, Phosphorylation, Adult, Matrix Metalloproteinase 8, Host-Pathogen Interactions, Immunity, Innate, AMP-Activated Protein Kinases, Proteolysis, Virology, 0605 Microbiology, 1107 Immunology, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: PLoS Pathogens
Article Number: e1004917
ISSN: 1553-7374
Language: eng
Dates:
DateEvent
21 May 2015Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
085777/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 25996154
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/107470
Publisher's version: https://doi.org/10.1371/journal.ppat.1004917

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