Universidad Peruana Cayetano Heredia

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

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dc.contributor.author Ong, Catherine W. M.
dc.contributor.author Elkington, Paul T.
dc.contributor.author Brilha, Sara
dc.contributor.author Ugarte Gil, Cesar Augusto
dc.contributor.author Tome-Esteban, Maite T.
dc.contributor.author Tezera, Liku B.
dc.contributor.author Pabisiak, Przemyslaw J.
dc.contributor.author Moores, Rachel C.
dc.contributor.author Sathyamoorthy, Tarangini
dc.contributor.author Patel, Vimal
dc.contributor.author Gilman, Robert Hugh
dc.contributor.author Porter, Joanna C.
dc.contributor.author Friedland, Jon S.
dc.date.accessioned 2019-02-06T14:53:12Z
dc.date.available 2019-02-06T14:53:12Z
dc.date.issued 2015
dc.identifier.uri https://hdl.handle.net/20.500.12866/5404
dc.description.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. en_US
dc.language.iso eng
dc.publisher Public Library of Science
dc.relation.ispartofseries PLoS Pathogens
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Adult en_US
dc.subject Humans en_US
dc.subject Cohort Studies en_US
dc.subject Cells, Cultured en_US
dc.subject Host-Pathogen Interactions/drug effects en_US
dc.subject Active Transport, Cell Nucleus/drug effects en_US
dc.subject AMP-Activated Protein Kinases/metabolism en_US
dc.subject Enzyme Inhibitors/pharmacology en_US
dc.subject Extracellular Matrix Proteins/metabolism en_US
dc.subject Immunity, Innate/drug effects en_US
dc.subject Lung/drug effects/immunology/metabolism/pathology en_US
dc.subject Matrix Metalloproteinase 8/chemistry/metabolism en_US
dc.subject Mycobacterium tuberculosis/drug effects/immunology/physiology en_US
dc.subject Neutrophil Infiltration/drug effects en_US
dc.subject Neutrophils/enzymology/immunology/metabolism/pathology en_US
dc.subject NF-kappa B/metabolism en_US
dc.subject Phosphorylation/drug effects en_US
dc.subject Protein Processing, Post-Translational/drug effects en_US
dc.subject Proteolysis/drug effects en_US
dc.subject Respiratory Mucosa/drug effects/immunology/metabolism/pathology en_US
dc.subject Sputum/enzymology en_US
dc.subject Tuberculosis, Pulmonary/drug therapy/immunology/metabolism/pathology en_US
dc.title Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1371/journal.ppat.1004917
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.01.09
dc.relation.issn 1553-7374


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