Coordinated induction of extracellular proteolysis systems during experimental autoimmune encephalomyelitis in mice

Plasminogen activators (PAs) and matrix metalloproteinases (MMPs) are consi dered to play an important role in the pathogenesis of multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is widely used as an animal model of multiple sclerosis. Whereas several studies have addressed the ex pression of various MMPs and their inhibitors in the pathogenesis of PA, th e expression of the molecules of the PA system during EAE has not been repo rted previously. The present study was undertaken to investigate the expres sion of the molecules of the PA system (tPA, uPA, PAI-1, uPAR, LRP), as wel l as several members of the MMP family and their inhibitors in the course o f actively induced EAE in BALB/c mice. During clinical EAE, the PA system w as up-regulated in the central nervous system at several levels. Induction of expression of tPA and PAI-1 transcripts was detected in activated astroc ytes in the white matter. Inflammatory cells expressed uPA receptor, uPAR. In situ zymography demonstrated the presence of increased tPA and uPA activ ities in the areas of the inflammatory damage. Accumulation of fibrin, fibr onectin, and vitronectin immunoreactivity was seen in perivascular matrices of symptomatic animals. In addition, transcription of MT1-MMP and metalloe lastase (in inflammatory cells), and TIMP-1 (in activated astrocytes) was i nduced during EAE. Increased gelatinolytic activity was detected at the sit es of inflammatory cell accumulation by in situ zymography of fluorescently labeled gelatin; substrate gel zymography identified the up-regulated gela tinolytic activity as gelatinase B. Overall, our study demonstrates concurr ent induction of PA and MMP systems during active EAE, supporting further t he concept that the neuroinflammatory damage in EAE involves altered balanc e between multiple extracellular proteases and their inhibitors.