MMP-1 drives immunopathology in human tuberculosis and transgenic mice

Elkington, Paul, Shiomi, Takayuki, Breen, Ronan, Nuttall, Robert K., Ugarte-Gil, Cesar Augusto, Walker, Naomi F., Saraiva, Luisa, Pedersen, Bernadette, Mauri, Francesco, Lipman, Marc, Edwards, Dylan R. ORCID: https://orcid.org/0000-0002-3292-2064, Robertson, Brian D., D’Armiento, Jeanine and Friedland, Jon S. (2011) MMP-1 drives immunopathology in human tuberculosis and transgenic mice. Journal of Clinical Investigation, 121 (5). pp. 1827-1833. ISSN 0021-9738

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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.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Biological Sciences
UEA Research Groups:	Faculty of Science > Research Groups > Cells and Tissues Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies
Depositing User:	Users 2731 not found.
Date Deposited:	12 Oct 2011 11:53
Last Modified:	21 Apr 2023 05:33
URI:	https://ueaeprints.uea.ac.uk/id/eprint/35003
DOI:	10.1172/JCI45666

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