title: Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.
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.
authors.affiliation: 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.
authors.forename: Catherine W M
authors.initials: CW
authors.lastname: Ong
authors.affiliation: 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.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.affiliation: Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Brilha
authors.affiliation: 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.
authors.forename: Cesar
authors.initials: C
authors.lastname: Ugarte-Gil
authors.affiliation: The Heart Hospital, University College London Hospitals, London, United Kingdom.
authors.forename: Maite T
authors.initials: MT
authors.lastname: Tome-Esteban
authors.affiliation: 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.
authors.forename: Liku B
authors.initials: LB
authors.lastname: Tezera
authors.affiliation: Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Przemyslaw J
authors.initials: PJ
authors.lastname: Pabisiak
authors.affiliation: Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Moores
authors.affiliation: Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Tarangini
authors.initials: T
authors.lastname: Sathyamoorthy
authors.affiliation: The Heart Hospital, University College London Hospitals, London, United Kingdom.
authors.forename: Vimal
authors.initials: V
authors.lastname: Patel
authors.affiliation: 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.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Gilman
authors.affiliation: Centre for Inflammation and Tissue Repair, Department of Medicine, University College London, London, United Kingdom.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Porter
authors.affiliation: Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D002478:Cells, Cultured; D015331:Cohort Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000737:chemistry / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013183:Sputum / Q000201:enzymology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D016328:NF-kappa B; D055372:AMP-Activated Protein Kinases; C488762:MMP8 protein, human; D020784:Matrix Metalloproteinase 8