MMP-1 drives immunopathology in human tuberculosis and transgenic mice
Paul Elkington, … , Jeanine D’Armiento, Jon S. Friedland
Paul Elkington, … , Jeanine D’Armiento, Jon S. Friedland
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):1827-1833. https://doi.org/10.1172/JCI45666.
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Research Article

MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Abstract

Mycobacterium tuberculosis can cause lung tissue damage to spread, but the mechanisms driving this immunopathology are poorly understood. The breakdown of lung matrix involves MMPs, which have a unique ability to degrade fibrillar collagens at neutral pH. To determine whether MMPs play a role in the immunopathology of tuberculosis (TB), we profiled MMPs and their inhibitors, the tissue inhibitor of metalloproteinases (TIMPs), in sputum and bronchoalveolar lavage fluid from patients with TB and symptomatic controls. MMP-1 concentrations were significantly increased in both HIV-negative and HIV-positive patients with TB, while TIMP concentrations were lower in HIV-negative TB patients. In primary human monocytes, M. tuberculosis infection selectively upregulated MMP1 gene expression and secretion, and Ro32-3555, a specific MMP inhibitor, suppressed M. tuberculosis–driven MMP-1 activity. Since the mouse MMP-1 ortholog is not expressed in the lung and mice infected with M. tuberculosis do not develop tissue destruction equivalent to humans, we infected transgenic mice expressing human MMP-1 with M. tuberculosis to investigate whether MMP-1 caused lung immunopathology. In the MMP-1 transgenic mice, M. tuberculosis infection increased MMP-1 expression, resulting in alveolar destruction in lung granulomas and significantly greater collagen breakdown. In summary, MMP-1 may drive tissue destruction in TB and represents a therapeutic target to limit immunopathology.

Authors

Paul Elkington, Takayuki Shiomi, Ronan Breen, Robert K. Nuttall, Cesar Augusto Ugarte-Gil, Naomi F. Walker, Luísa Saraiva, Bernadette Pedersen, Francesco Mauri, Marc Lipman, Dylan R. Edwards, Brian D. Robertson, Jeanine D’Armiento, Jon S. Friedland

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Figure 2

MMP-1 is increased in HIV-TB coinfection and is enzymatically active.

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MMP-1 is increased in HIV-TB coinfection and is enzymatically active. (A...
(A) In HIV-positive patients, MMP-1 was increased in lung secretions from patients with TB compared with that in respiratory symptomatics. (B) Casein zymography. 20 μl induced sputum from respiratory symptomatics (Cont) or TB-infected patients (TB) was resolved on a casein zymogram and incubated in collagenase buffer at 37°C for 40 hours. After staining with Coomassie blue, induced sputum from patients with TB had greater caseinolytic activity, demonstrating that the increased MMP-1 detected by luminex array retains potential proteolytic activity. (C) Chest radiographs of patients with TB were scored for severity. MMP-1 concentrations in respiratory secretions were higher in patients with more extensive disease. Differences analyzed by Mann-Whitney U test are shown. For box-and-whisker plots, the box outline represents the 25th and 75th percentiles, the central line represents the median value, and the whiskers represent minimum and maximum values.