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

Catherine W M Ong1, Paul T Elkington2, Sara Brilha3

  • 1Infectious 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.

Plos Pathogens
|May 22, 2015
PubMed

Insights

Neutrophil-derived matrix metalloproteinase-8 (MMP-8) drives tissue destruction in tuberculosis (TB) lung cavities. Inhibiting MMP-8 with doxycycline offers a potential host-directed therapy for TB by reducing collagen breakdown.

Area of Science:

  • Immunopathology
  • Tuberculosis Research
  • Matrix Destruction Mechanisms

Background:

  • Pulmonary cavities in tuberculosis (TB) are linked to high bacterial load and disease spread.
  • The precise mechanisms of matrix destruction leading to cavitation remain unclear.
  • Neutrophil infiltration correlates with adverse outcomes in TB patients.

Purpose of the Study:

  • To investigate neutrophil-dependent pathways contributing to matrix destruction in TB.
  • To identify specific molecules involved in TB-associated tissue damage.
  • To explore potential host-directed therapeutic targets for TB.

Main Methods:

  • Utilized a cellular model, analyzed a cohort of 108 TB patients, and examined patient lung biopsies.
  • Assessed neutrophil-derived matrix metalloproteinase-8 (MMP-8) secretion and its role in matrix degradation.
  • Investigated the involvement of NF-kB, neutrophil extracellular traps (NETs), and AMPK in MMP-8 production.

Main Results:

  • Neutrophil-derived MMP-8 secretion was elevated in TB patients and mediated matrix destruction in vitro and in vivo.
  • Doxycycline, an MMP inhibitor, abrogated TB-induced collagen destruction.
  • Neutrophil extracellular traps (NETs) containing MMP-8 were increased in TB patients, and neutrophils were found at the edge of pulmonary cavities.
  • AMPK signaling positively regulated neutrophil MMP-8 secretion.

Conclusions:

  • Neutrophil-derived MMP-8 plays a critical role in the immunopathology and matrix destruction associated with TB.
  • MMP-8 is a potential therapeutic target for host-directed treatment strategies in TB.
  • AMPK signaling is a key regulator of MMP-8 secretion by neutrophils in the context of TB.

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