title: Membrane Type 1 Matrix Metalloproteinase Regulates Monocyte Migration and Collagen Destruction in Tuberculosis.
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.
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Tarangini
authors.initials: T
authors.lastname: Sathyamoorthy
authors.affiliation: National Institute for Health Research Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom;
authors.forename: Liku B
authors.initials: LB
authors.lastname: Tezera
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom; Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa;
authors.forename: Naomi F
authors.initials: NF
authors.lastname: Walker
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Sara
authors.initials: S
authors.lastname: Brilha
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Luisa
authors.initials: L
authors.lastname: Saraiva
authors.affiliation: Department of Histopathology, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Mauri
authors.affiliation: Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa; Department of Medicine, Imperial College London, London W12 0NN, United Kingdom; Medical Research Council, National Institute for Medical Research, London NW7 1AA, United Kingdom; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom;
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
authors.affiliation: Infectious Diseases and Immunity, Imperial College London, London W12 0NN, United Kingdom; National Institute for Health Research Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, United Kingdom; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom p.elkington@soton.ac.uk.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
mesh_terms: D000328:Adult; D000368:Aged; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D017364:Collagenases / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D013183:Sputum / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D003094:Collagen; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14