MMP-1 drives immunopathology in human tuberculosis and transgenic mice
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
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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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 3

M. tuberculosis selectively upregulates MMP1 gene expression.

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M. tuberculosis selectively upregulates MMP1 gene expression. Prima...
Primary human monocytes were infected with M. tuberculosis, and total RNA was extracted at 24 hours. (A) Gene expression profiling of all human MMPs, TIMPs, and ADAMs. Cycle threshold analysis for each gene is demonstrated, from white indicating low expression to black indicating high expression, and data are the mean of 3 donors infected on separate occasions. MMP1 is the collagenase most highly constitutively expressed. M. tuberculosis–infected cells upregulated MMP1, MMP3, MMP7, MMP8, MMP10, MMP12, and MMP14 compared with uninfected cells. Expression of ADAM17 and ADAM19 is also increased in infected monocytes. (B) M. tuberculosis upregulates MMP1 mRNA more potently than other secreted collagenases. MMP1 mRNA levels increased 100 fold in each donor 24 hours after infection. No compensatory increase in expression of inhibitors TIMP1–TIMP4 and RECK is demonstrated. Fold change in gene expression levels of all other MMPs, TIMPs, and ADAMs are shown in Supplemental Figure 2. ***P < 0.001.