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PLoS Pathog. 2015 May 21;11(5):e1004917. doi: 10.1371/journal.ppat.1004917. eCollection 2015 May.

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

Author information

1
Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom; Division of Infectious Diseases, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2
Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom; National Institute of Health Research (NIHR) Respiratory Biomedical Research Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
3
Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
4
Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom; Instituto de Medicina Tropical Alexander Von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
5
The Heart Hospital, University College London Hospitals, London, United Kingdom.
6
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America; Asociación Benéfica Proyectos en Informatica, Salud, Medicina, y Agricultura (PRISMA), Universidad Peruana Cayetano Heredia, Lima, Peru.
7
Centre for Inflammation and Tissue Repair, Department of Medicine, University College London, London, United Kingdom.

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.

PMID:
25996154
PMCID:
PMC4440706
DOI:
10.1371/journal.ppat.1004917
[Indexed for MEDLINE]
Free PMC Article

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