Brain, Vol. 124, No. 10, 1978-1988,
October 2001
© 2001 Oxford University Press
Plasminogen activators in multiple sclerosis lesions
Implications for the inflammatory response and axonal damage
1 Department of Neurochemistry, Institute of Neurology, University College London, UK, 2 Gaubius Laboratory, TNO-PG, Leiden, The Netherlands and 3 Department of Molecular Medicine, DIBIT, San Raffaele Scientific Institute, Milan, Italy
Correspondence to:
Dr Djordje Gveric, Neuroinflammation Group, Department of Neurochemistry, Institute of Neurology, London WC1N 1PJ, UK E-mail: d.gueric{at}ion.ucl.ac.uk
Components of the plasminogen activator (PA) and matrix metalloprotease (MMP) cascade have been characterized in multiple sclerosis lesions by immunohistochemistry, enzyme-linked immunosorbent assay and enzyme activity assays in order to establish a functional role for the enzyme sequence in lesion development. Highly significant quantitative increases in urokinase PA (uPA), urokinase receptor (uPAR) and plasminogen activator inhibitor-1 were detected in acute multiple sclerosis lesions (P < 0.0001) and in uPAR in normal-appearing white matter (P < 0.0001) compared with control tissue. All three proteins were immunolocalized to mononuclear cells in perivascular cuffs and to macrophages in the lesion parenchyma. MMP-9 and the tissue inhibitor of metalloprotease-1 also increased during lesion development but the enzyme was present largely in the inactive pro-form. In contrast to uPA, the concentration and activity of tissue PA (tPA), the most abundant plasminogen activator in normal control brain, were reduced in multiple sclerosis specimens. In acute lesions tPA co-localized with fibrin(ogen) on large diameter axons also stained with SMI-32, an immunohistochemical marker of axonal damage. The uPA–uPAR complex, concentrated on inflammatory cells in the perivascular zone of the evolving lesion, may facilitate cellular infiltration into the CNS which is amplified by MMP- mediated degradation of blood vessel matrix. tPA localization on injured axons may be a marker of axonal damage or represent a protective mechanism aimed at removal of fibrin deposits and restoration of axonal function.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Lovrecic, S. Ristic, N. Starcevic-Cizmarevic, B. Brajenovic-Milic, Sasa Sega Jazbec, J. Sepcic, M. Kapovic, and B. Peterlin PAI and TPA gene polymorphisms in multiple sclerosis Multiple Sclerosis, March 1, 2008; 14(2): 243 - 247. [Abstract] [PDF]
|
|
|
|
|
|
V. Lehmensiek, S. Sussmuth, G. Tauscher, J. Brettschneider, S. Felk, F. Gillardon, and H. Tumani Cerebrospinal fluid proteome profile in multiple sclerosis Multiple Sclerosis, August 1, 2007; 13(7): 840 - 849. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Krapf, S. P. Morrissey, O. Zenker, T. Zwingers, R. Gonsette, H. -P. Hartung, and the MIMS Study Group Effect of mitoxantrone on MRI in progressive MS: Results of the MIMS trial Neurology, September 13, 2005; 65(5): 690 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. East, D. Baker, G. Pryce, H. R. Lijnen, M. L. Cuzner, and D. Gveric A Role for the Plasminogen Activator System in Inflammation and Neurodegeneration in the Central Nervous System during Experimental Allergic Encephalomyelitis Am. J. Pathol., August 1, 2005; 167(2): 545 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gveric, B. M. Herrera, and M. L. Cuzner tPA Receptors and the Fibrinolytic Response in Multiple Sclerosis Lesions Am. J. Pathol., April 1, 2005; 166(4): 1143 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Petzold, M J Eikelenboom, G Keir, D Grant, R H C Lazeron, C H Polman, B M J Uitdehaag, E J Thompson, and G Giovannoni Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study J. Neurol. Neurosurg. Psychiatry, February 1, 2005; 76(2): 206 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fernandez-Monreal, J. P. Lopez-Atalaya, K. Benchenane, M. Cacquevel, F. Dulin, J.-P. Le Caer, J. Rossier, A.-C. Jarrige, E. T. MacKenzie, N. Colloc'h, et al. Arginine 260 of the Amino-terminal Domain of NR1 Subunit Is Critical for Tissue-type Plasminogen Activator-mediated Enhancement of N-Methyl-D-aspartate Receptor Signaling J. Biol. Chem., December 3, 2004; 279(49): 50850 - 50856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Adams, M. Passino, B. D. Sachs, T. Nuriel, and K. Akassoglou Fibrin Mechanisms and Functions in Nervous System Pathology Mol. Interv., June 1, 2004; 4(3): 163 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A H G Hansma, Y van Hensbergen, B C Kuenen, P J van Diest, R Hanemaaijer, S Meijer, H M Pinedo, and K Hoekman A patient with a VEGF and endostatin producing gastrointestinal autonomic nerve tumour J. Clin. Pathol., May 1, 2004; 57(5): 536 - 538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Akassoglou, R. A. Adams, J. Bauer, P. Mercado, V. Tseveleki, H. Lassmann, L. Probert, and S. Strickland Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis PNAS, April 27, 2004; 101(17): 6698 - 6703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Gveric, B. Herrera, A. Petzold, D. A. Lawrence, and M. L. Cuzner Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors Brain, July 1, 2003; 126(7): 1590 - 1598. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Medana and M. M. Esiri Axonal damage: a key predictor of outcome in human CNS diseases Brain, March 1, 2003; 126(3): 515 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. van Hensbergen, H. J. Broxterman, R. Hanemaaijer, A. S. Jorna, N. A. van Lent, H. M. W. Verheul, H. M. Pinedo, and K. Hoekman Soluble Aminopeptidase N/CD13 in Malignant and Nonmalignant Effusions and Intratumoral Fluid Clin. Cancer Res., December 1, 2002; 8(12): 3747 - 3754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Winkler, S. Kastenbauer, U. Koedel, and H. W. Pfister Role of the urokinase plasminogen activator system in patients with bacterial meningitis Neurology, November 12, 2002; 59(9): 1350 - 1355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Petzold, M. J. Eikelenboom, D. Gveric, G. Keir, M. Chapman, R. H. C. Lazeron, M. L. Cuzner, C. H. Polman, B. M. J. Uitdehaag, E. J. Thompson, et al. Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations Brain, July 1, 2002; 125(7): 1462 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Scarisbrick, S. I. Blaber, C. F. Lucchinetti, C. P. Genain, M. Blaber, and M. Rodriguez Activity of a newly identified serine protease in CNS demyelination Brain, June 1, 2002; 125(6): 1283 - 1296. [Abstract] [Full Text] [PDF]
|
|