tPA receptors and the fibrinolytic response in multiple sclerosis lesions.
Axonal damage in multiple sclerosis (MS) lesions is associated with failure of fibrinolysis because of the inhibition of the plasminogen activator system. Plasma membrane receptors for tissue plasminogen activator (tPA) and plasminogen concentrate proteolytic activity on the cell surface and provide protection from inhibitors that in turn may locally enhance the fibrinolytic response. Therefore, we have investigated expression of two of these receptors in MS lesions, annexin II tetramer (AIIt) and low-density lipoprotein receptor-related protein (LRP). In acute MS lesions both AIIt and LRP were immunolocalized on macrophages and astrocytes while LRP was additionally found on neuronal cells in cortical gray matter. Western blot analysis confirmed a significant increase in AIIt in MS lesions and in a proportion of normal-appearing white matter samples, with a highly significant correlation between annexin II levels and factors associated with impeded fibrinolysis, such as plasminogen activator inhibitor-1. Immunoblotting analysis of plasmin(ogen) revealed increased levels of lysine-plasminogen in samples expressing high AIIt protein levels. Our results suggest that limited availability of tPA in MS lesions because of formation of tPA-plasminogen activator inhibitor-1 complexes reduces capability of tPA receptors to generate plasmin, which further diminishes fibrinolytic capacity in active MS lesions and possibly leads to axonal damage.
Gveric
Djordje
D
Department of Neuroinflammation, Institute of Neurology, UCL, 1 Wakefield St., London WC1N 1PJ, UK. d.gueric@ion.ucl.ac.uk
Herrera
Blanca M
BM
Cuzner
M Louise
ML
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017306:Annexin A2 / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D006801:Humans; D007150:Immunohistochemistry; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator
C472822:ANXA2 protein, human; D017306:Annexin A2; D026563:LDL-Receptor Related Protein-Associated Protein; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D010958:Plasminogen; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin