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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Active Transport, Cell Nucleus / drug effects
  • Adult
  • Cells, Cultured
  • Cohort Studies
  • Enzyme Inhibitors / pharmacology
  • Extracellular Matrix Proteins / metabolism*
  • Host-Pathogen Interactions* / drug effects
  • Humans
  • Immunity, Innate / drug effects
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Matrix Metalloproteinase 8 / chemistry
  • Matrix Metalloproteinase 8 / metabolism*
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / immunology
  • Mycobacterium tuberculosis / physiology*
  • NF-kappa B / metabolism
  • Neutrophil Infiltration / drug effects
  • Neutrophils / enzymology*
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Proteolysis / drug effects
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Sputum / enzymology
  • Tuberculosis, Pulmonary / drug therapy
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / metabolism*
  • Tuberculosis, Pulmonary / pathology


  • Enzyme Inhibitors
  • Extracellular Matrix Proteins
  • NF-kappa B
  • AMP-Activated Protein Kinases
  • MMP8 protein, human
  • Matrix Metalloproteinase 8