Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 56, Issue 2, Pages 223-232Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2016-0162OC
Keywords
matrix metalloproteinases; early secretory antigenic target-6; tuberculosis
Funding
- Portuguese Foundation for Science and Technology
- Rosetrees Trust
- Breathing Matters charities
- Medical Research Council (UK) Clinical Research Training Fellowships
- Wellcome Trust Clinical Research Training Fellowship in Tropical Medicine and Public Health [094,000]
- Wellcome Trust Clinical Research Training Fellowship
- Francis Crick Institute
- Cancer Research UK [FC00110218]
- United Kingdom Medical Research Council [FC00110218]
- Wellcome Trust [FC00110218, 104,803]
- South African Medical Research Council Strategic Health Innovation Partnerships
- National Research Foundation of South Africa [96,841]
- Imperial Biomedical Research Centre
- MRC [G0900429] Funding Source: UKRI
- Medical Research Council [G0900429] Funding Source: researchfish
- Rosetrees Trust [M341] Funding Source: researchfish
- The Francis Crick Institute [10218] Funding Source: researchfish
- Wellcome Trust [104803/Z/14/Z] Funding Source: researchfish
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Tuberculosis (TB) causes disease worldwide, and multidrug resistance is an increasing problem. Matrix metalloproteinases (MMPs), particularly the collagenase MMP-1, cause lung extracellular matrix destruction, which drives disease transmission and morbidity. The role in such tissue damage of the stromelysin MMP-10, a key activator of the collagenase MMP-1, was investigated in direct Mycobacterium tuberculosis (Mtb)-infected macrophages and in conditioned medium from Mtb-infected monocyte-stimulated cells. Mtb infection increased MMP-10 secretion from primary human macrophages 29-fold, whereas Mtb-infected monocytes increased secretion by 4.5-fold from pulmonary epithelial cells and 10.5-fold from fibroblasts. Inhibition of MMP-10 activity decreased collagen breakdown. In two independent cohorts of patients with TB from different continents, MMP-10 was increased in both induced sputum and bronchoalveolar lavage fluid compared with control subjects and patients with other respiratory diseases (both P < 0.05). Mtb drove 3.5-fold greater MMP-10 secretion from human macrophages than the vaccine strain bacillus Calmette-Guerin (P < 0.001), whereas both mycobacteria up-regulated TNF-? secretion equally. Using overlapping, short, linear peptides covering the sequence of early secretory antigenic target-6, a virulence factor secreted by Mtb, but not bacillus Calmette-Guerin, we found that stimulation of human macrophages with a single specific 15-amino acid peptide sequence drove threefold greater MMP-10 secretion than any other peptide (P < 0.001). Mtb-driven MMP-10 secretion was inhibited in a dose-dependent manner by p38 and extracellular signal-related kinase mitogen-activated protein kinase blockade (P < 0.001 and P < 0.01 respectively), but it was not affected by inhibition of NF-?B. In summary, Mtb activates inflammatory and stromal cells to secrete MMP-10, and this is partly driven by the virulence factor early secretory antigenic target-6, implicating it in TB-associated tissue destruction.
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