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MMP-1 drives immunopathology in human tuberculosis and transgenic mice.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2011 May; Vol. 121 (5), pp. 1827-33. Date of Electronic Publication: 2011 Apr 25. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Bronchoalveolar Lavage Fluid
Cell Movement
Enzyme Inhibitors pharmacology
HIV Infections enzymology
HIV Seropositivity
Humans
Hydrogen-Ion Concentration
Imidazoles pharmacology
Immune System
Mice
Mice, Transgenic
Monocytes cytology
Gene Expression Regulation, Enzymologic
Matrix Metalloproteinase 1 metabolism
Tuberculosis enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 121
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 21519144
- Full Text :
- https://doi.org/10.1172/JCI45666