Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in Human Pulmonary Tuberculosis
Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in Human Pulmonary Tuberculosis
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.
Ong, C.W.
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Elkington, P.T.
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Brilha, S.
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Ugarte-Gil, C.
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Tome-Esteban, M.T.
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Tezera, L.B
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Pabisiak, P.J.
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Moores, R.C.
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Sathyamoorthy, T.
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Patel, V.
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Gilman, R.H.
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Porter, J.C.
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Friedland, J.S.
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21 May 2015
Ong, C.W.
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Elkington, P.T.
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Brilha, S.
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Ugarte-Gil, C.
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Tome-Esteban, M.T.
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Tezera, L.B
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Pabisiak, P.J.
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Moores, R.C.
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Sathyamoorthy, T.
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Patel, V.
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Gilman, R.H.
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Porter, J.C.
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Friedland, J.S.
e64a7af8-b969-4426-82e6-5ebe819799c9
Ong, C.W., 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. and Friedland, J.S.
(2015)
Neutrophil-derived MMP-8 drives AMPK-dependent matrix destruction in Human Pulmonary Tuberculosis.
PLOS Pathogens, 11, [e1004917].
(doi:10.1371/journal.ppat.1004917).
(PMID:25996154)
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.
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Accepted/In Press date: 27 April 2015
e-pub ahead of print date: 21 May 2015
Published date: 21 May 2015
Organisations:
Clinical & Experimental Sciences
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Local EPrints ID: 377480
URI: http://eprints.soton.ac.uk/id/eprint/377480
ISSN: 1553-7366
PURE UUID: 211e5ad5-3b03-4bef-afda-f222afc5b73b
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Date deposited: 15 Jun 2015 12:01
Last modified: 15 Mar 2024 03:45
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Contributors
Author:
C.W. Ong
Author:
S. Brilha
Author:
C. Ugarte-Gil
Author:
M.T. Tome-Esteban
Author:
P.J. Pabisiak
Author:
R.C. Moores
Author:
T. Sathyamoorthy
Author:
V. Patel
Author:
R.H. Gilman
Author:
J.C. Porter
Author:
J.S. Friedland
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