Plasminogen activators in multiple sclerosis lesions - Implications for the inflammatory response and axonal damage

Components of the plasminogen activator (PA) and matrix metalloprotease (MM P) cascade have been characterized in multiple sclerosis lesions by immunoh istochemistry, 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 det ected in acute multiple sclerosis lesions (P < 0.0001) and in uPAR in norma l-appearing white matter (P < 0.0001) compared with control tissue. All thr ee proteins were immunolocalized to mononuclear cells in perivascular cuffs and to macrophages in the lesion parenchyma. MMP-9 and the tissue inhibito r of metalloprotease-1 also increased during lesion development but the enz yme was present largely in the inactive pro-form. In contrast to uPA, the c oncentration and activity of tissue PA (WA), the most abundant plasminogen activator in normal control brain, were reduced in multiple sclerosis speci mens. In acute lesions tPA colocalized with fibrin(ogen) on large diameter axons also stained with SMI-32, an immunohistochemical marker of axonal dam age. The uPA-uPAR complex, concentrated on inflammatory cells in the periva scular zone of the evolving lesion, may facilitate cellular infiltration in to the CNS which is amplified by MMP-mediated degradation of blood vessel m atrix. tPA localization on injured axons may be a marker of axonal damage o r represent a protective mechanism aimed at removal of fibrin deposits and restoration of axonal function.