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Membrane type 1 matrix metalloproteinase regulates monocyte migration and collagen destruction in tuberculosis

Membrane type 1 matrix metalloproteinase regulates monocyte migration and collagen destruction in tuberculosis
Membrane type 1 matrix metalloproteinase regulates monocyte migration and collagen destruction in tuberculosis
Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granuloma formation is the pathological hallmark of Mycobacterium tuberculosis infection. The membrane type 1 matrix metalloproteinase (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagen destruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-fold compared with matched controls and correlated positively with extent of lung infiltration on chest radiographs (r = 0.483; p < 0.05). M. tuberculosis infection of primary human monocytes increased MT1-MMP surface expression 31.7-fold and gene expression 24.5-fold. M. tuberculosis-infected monocytes degraded collagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralization decreased collagen degradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed in macrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase in MT1-MMP surface expression dependent on p38 MAPK and G protein-coupled receptor-dependent signaling. Monocytes migrating toward agarose beads impregnated with conditioned media from M. tuberculosis-infected monocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this M. tuberculosis network-dependent monocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central to two key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration.
0022-1767
882-891
Sathyamoorthy, T
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Tezera, L.B.
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Walker, N
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Brilha, S.
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Saraiva, L.
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Mauri, F.A.
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Wilkinson, R.J.
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Friedland, J.S.
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Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Sathyamoorthy, T
0a0a5b66-45b4-4f92-a842-5115dff399e9
Tezera, L.B.
c5598dbf-23a8-4934-96a4-7c783bf9e776
Walker, N
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Brilha, S.
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Saraiva, L.
a44071de-689c-4a91-bff0-708ccefd3908
Mauri, F.A.
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Wilkinson, R.J.
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Friedland, J.S.
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Elkington, P.T.
60828c7c-3d32-47c9-9fcc-6c4c54c35a15

Sathyamoorthy, T, Tezera, L.B., Walker, N, Brilha, S., Saraiva, L., Mauri, F.A., Wilkinson, R.J., Friedland, J.S. and Elkington, P.T. (2015) Membrane type 1 matrix metalloproteinase regulates monocyte migration and collagen destruction in tuberculosis. Journal of Immunology, 195 (3), 882-891. (doi:10.4049/jimmunol.1403110). (PMID:26091717)

Record type: Article

Abstract

Tuberculosis (TB) remains a global pandemic and drug resistance is rising. Multicellular granuloma formation is the pathological hallmark of Mycobacterium tuberculosis infection. The membrane type 1 matrix metalloproteinase (MT1-MMP or MMP-14) is a collagenase that is key in leukocyte migration and collagen destruction. In patients with TB, induced sputum MT1-MMP mRNA levels were increased 5.1-fold compared with matched controls and correlated positively with extent of lung infiltration on chest radiographs (r = 0.483; p < 0.05). M. tuberculosis infection of primary human monocytes increased MT1-MMP surface expression 31.7-fold and gene expression 24.5-fold. M. tuberculosis-infected monocytes degraded collagen matrix in an MT1-MMP-dependent manner, and MT1-MMP neutralization decreased collagen degradation by 73%. In human TB granulomas, MT1-MMP immunoreactivity was observed in macrophages throughout the granuloma. Monocyte-monocyte networks caused a 17.5-fold increase in MT1-MMP surface expression dependent on p38 MAPK and G protein-coupled receptor-dependent signaling. Monocytes migrating toward agarose beads impregnated with conditioned media from M. tuberculosis-infected monocytes expressed MT1-MMP. Neutralization of MT1-MMP activity decreased this M. tuberculosis network-dependent monocyte migration by 44%. Taken together, we demonstrate that MT1-MMP is central to two key elements of TB pathogenesis, causing collagen degradation and regulating monocyte migration.

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Accepted/In Press date: 24 May 2015
e-pub ahead of print date: 19 June 2015
Published date: 1 August 2015
Additional Information: Funded by Medical Research Council Clinical Research Training Fellowship: The Role of Membrane-type Matrix Metalloproteinases in the Pathogenesis of Tuberculosis (G0900429)
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 378311
URI: https://eprints.soton.ac.uk/id/eprint/378311
ISSN: 0022-1767
PURE UUID: c55173fe-734c-45c6-9312-25153e78a8b3
ORCID for L.B. Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for P.T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 23 Jun 2015 10:26
Last modified: 06 Jun 2018 12:28

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Contributors

Author: T Sathyamoorthy
Author: L.B. Tezera ORCID iD
Author: N Walker
Author: S. Brilha
Author: L. Saraiva
Author: F.A. Mauri
Author: R.J. Wilkinson
Author: J.S. Friedland
Author: P.T. Elkington ORCID iD

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