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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
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.
1553-7366
e1004917-[21pp]
Ong, C.W.
79597af0-4e5b-42ae-a8f2-f93682fc1d5c
Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Brilha, S.
df434c3e-e098-46f8-bc07-be1d9c10433a
Ugarte-Gil, C.
d2125fab-b359-4e2c-aa74-ececbae181a9
Tome-Esteban, M.T.
63c909f7-e1a5-4ae6-baf7-6998fe034ddb
Tezera, L.B
c5598dbf-23a8-4934-96a4-7c783bf9e776
Pabisiak, P.J.
84b0fe76-3173-415a-9cab-35f73dc218cf
Moores, R.C.
e1200abb-7d95-4ebe-9578-1f6be52f1d00
Sathyamoorthy, T.
83d53741-7a15-4b98-8000-d66f377c2fa1
Patel, V.
cd67a79a-66ac-48d8-8230-4fcc76c868d8
Gilman, R.H.
53a5320a-794e-4082-9bf7-8799d540bb1f
Porter, J.C.
671f815d-348e-40da-bb49-de7400430e21
Friedland, J.S.
e64a7af8-b969-4426-82e6-5ebe819799c9
Ong, C.W.
79597af0-4e5b-42ae-a8f2-f93682fc1d5c
Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Brilha, S.
df434c3e-e098-46f8-bc07-be1d9c10433a
Ugarte-Gil, C.
d2125fab-b359-4e2c-aa74-ececbae181a9
Tome-Esteban, M.T.
63c909f7-e1a5-4ae6-baf7-6998fe034ddb
Tezera, L.B
c5598dbf-23a8-4934-96a4-7c783bf9e776
Pabisiak, P.J.
84b0fe76-3173-415a-9cab-35f73dc218cf
Moores, R.C.
e1200abb-7d95-4ebe-9578-1f6be52f1d00
Sathyamoorthy, T.
83d53741-7a15-4b98-8000-d66f377c2fa1
Patel, V.
cd67a79a-66ac-48d8-8230-4fcc76c868d8
Gilman, R.H.
53a5320a-794e-4082-9bf7-8799d540bb1f
Porter, J.C.
671f815d-348e-40da-bb49-de7400430e21
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-[21pp]. (PMID:25996154)

Record type: Article

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
Published date: 21 May 2015
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 377480
URI: https://eprints.soton.ac.uk/id/eprint/377480
ISSN: 1553-7366
PURE UUID: 211e5ad5-3b03-4bef-afda-f222afc5b73b
ORCID for P.T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for L.B Tezera: ORCID iD orcid.org/0000-0002-7898-6709

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Date deposited: 15 Jun 2015 12:01
Last modified: 06 Jun 2018 12:28

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Contributors

Author: C.W. Ong
Author: P.T. Elkington ORCID iD
Author: S. Brilha
Author: C. Ugarte-Gil
Author: M.T. Tome-Esteban
Author: L.B Tezera ORCID iD
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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