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MMP-1 drives immunopathology in human tuberculosis and transgenic mice

MMP-1 drives immunopathology in human tuberculosis and transgenic mice
MMP-1 drives immunopathology in human tuberculosis and transgenic mice
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.
0021-9738
1827-1833
Elkington, Paul
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Shiomi, Takayuki
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Breen, Ronan
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Nuttall, Robert K.
4014f16f-652a-4c0d-89ae-9c2485ebd569
Ugarte-Gil, Cesar Augusto
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Walker, Naomi F.
e586ffdf-ae4b-46fa-83a1-db72501d17c1
Saraiva, Luísa
b8d2793b-3acd-4c13-95cc-ed9f4621b66d
Pedersen, Bernadette
f8b181f9-aa3f-4969-98fd-844f358912f9
Mauri, Francesco
c1ddabd0-5459-4e83-9c51-20d8f1a36a78
Lipman, Marc
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Edwards, Dylan R.
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Robertson, Brian D.
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D’Armiento, Jeanine
be114eb0-bca9-49f2-80b8-931637e32dcb
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Shiomi, Takayuki
6264b232-b410-4ee6-9d8e-e79b3f84fbca
Breen, Ronan
0577fbf3-414c-416f-be6f-022f8c5e02e9
Nuttall, Robert K.
4014f16f-652a-4c0d-89ae-9c2485ebd569
Ugarte-Gil, Cesar Augusto
705952c4-d412-4f77-9226-852f2973e117
Walker, Naomi F.
e586ffdf-ae4b-46fa-83a1-db72501d17c1
Saraiva, Luísa
b8d2793b-3acd-4c13-95cc-ed9f4621b66d
Pedersen, Bernadette
f8b181f9-aa3f-4969-98fd-844f358912f9
Mauri, Francesco
c1ddabd0-5459-4e83-9c51-20d8f1a36a78
Lipman, Marc
5a10162e-e8d5-442b-a740-599848e9cdcd
Edwards, Dylan R.
b487d128-6527-42fc-aa7f-e07225990a6b
Robertson, Brian D.
b57bc6d3-006c-442e-bfc2-7485cd7fd3d2
D’Armiento, Jeanine
be114eb0-bca9-49f2-80b8-931637e32dcb
Friedland, Jon S.
9968669f-afe0-4163-9b35-3b476246fd4a

Elkington, Paul, Shiomi, Takayuki, Breen, Ronan, Nuttall, Robert K., Ugarte-Gil, Cesar Augusto, Walker, Naomi F., Saraiva, Luísa, Pedersen, Bernadette, Mauri, Francesco, Lipman, Marc, Edwards, Dylan R., 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), 1827-1833. (doi:10.1172/JCI45666).

Record type: Article

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.

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Published date: May 2011
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 340684
URI: http://eprints.soton.ac.uk/id/eprint/340684
ISSN: 0021-9738
PURE UUID: 6d0b5441-f7aa-4f42-a2cd-56e718e291c2
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 28 Jun 2012 15:45
Last modified: 15 Mar 2024 03:43

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Contributors

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

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