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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-05-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004917&type=printable |
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| author | Catherine W M Ong Paul T Elkington Sara Brilha Cesar Ugarte-Gil Maite T Tome-Esteban Liku B Tezera Przemyslaw J Pabisiak Rachel C Moores Tarangini Sathyamoorthy Vimal Patel Robert H Gilman Joanna C Porter Jon S Friedland |
| author_facet | Catherine W M Ong Paul T Elkington Sara Brilha Cesar Ugarte-Gil Maite T Tome-Esteban Liku B Tezera Przemyslaw J Pabisiak Rachel C Moores Tarangini Sathyamoorthy Vimal Patel Robert H Gilman Joanna C Porter Jon S Friedland |
| author_sort | Catherine W M Ong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-49b9d65c48af490b8e5a2e41ef0380b6 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-49b9d65c48af490b8e5a2e41ef0380b62025-08-20T03:46:13ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-05-01115e100491710.1371/journal.ppat.1004917Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.Catherine W M OngPaul T ElkingtonSara BrilhaCesar Ugarte-GilMaite T Tome-EstebanLiku B TezeraPrzemyslaw J PabisiakRachel C MooresTarangini SathyamoorthyVimal PatelRobert H GilmanJoanna C PorterJon S FriedlandPulmonary 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004917&type=printable |
| spellingShingle | Catherine W M Ong Paul T Elkington Sara Brilha Cesar Ugarte-Gil Maite T Tome-Esteban Liku B Tezera Przemyslaw J Pabisiak Rachel C Moores Tarangini Sathyamoorthy Vimal Patel Robert H Gilman Joanna C Porter Jon S Friedland Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathogens |
| title | Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. |
| title_full | Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. |
| title_fullStr | Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. |
| title_full_unstemmed | Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. |
| title_short | Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. |
| title_sort | neutrophil derived mmp 8 drives ampk dependent matrix destruction in human pulmonary tuberculosis |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1004917&type=printable |
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