title: The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention.
abstract: BACKGROUND
  Extracellular proteases such as plasminogen activators (PAs) and matrix metalloproteinases modulate cell-cell and cell-matrix interactions. Components of the PA/plasmin system have been shown to be increased in areas of inflammation, and have been suggested to play a role in inflammatory neurologic disorders such as epilepsy, stroke, brain trauma, Alzheimer's' disease and multiple sclerosis (MS). In the present study, we evaluated the involvement of the PA system in the animal model of MS, experimental autoimmune encephalomyelitis (EAE).
  
  
  METHODS
  EAE was induced by myelin oligodendrocyte glycoprotein (MOG) in mice deficient for the urokinase PA (uPA-/-), or the urokinase PA receptor (uPAR-/-). Mice were evaluated for EAE clinical signs and histopathologic parameters, and compared with wild-type (WT) EAE mice. Lymphocytes from the knockout (KO) and WT mice were analyzed for ex vivo restimulation, cytokine secretion, and antigen presentation. Finally, WT EAE mice were treated with PAI-1dp, an 18 amino acid peptide derived from the PA inhibitor protein (PAI-1).
  
  
  RESULTS
  EAE was aggravated in uPA-/- and uPAR-/- mice, and this was accompanied by more severe histopathologic features and microglial activation. By contrast, specific T- cell reactivity towards the encephalitogenic antigen MOG was markedly reduced in the KO animals, as shown by a marked reduction in proliferation and pro-inflammatory cytokine secretion in these mice. Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox. When the mice were treated with PAI-1, a peptide derived from the PA system, a marked and significant improvement in EAE was seen. The clinical improvement was linked to reduced T-cell reactivity, further emphasizing the importance of the PA system in immunomodulation during neuroinflammation.
  
  
  CONCLUSIONS
  Cumulatively, our results suggest a role for uPA and uPAR in EAE pathogenesis, as exacerbation of disease was seen in their absence. Furthermore, the successful amelioration of EAE by PAI-1 treatment suggests that the PA system can be considered a potential site for therapeutic intervention in the treatment of neuroimmune diseases.
authors.affiliation: Department of Neurology, Hadassah Medical Center, P,O, Box 12000, Jerusalem 91120, Israel. brenner@cc.huji.ac.il.
authors.forename: Devorah
authors.initials: D
authors.lastname: Gur-Wahnon
authors.forename: Tehila
authors.initials: T
authors.lastname: Mizrachi
authors.forename: Florence-Yehudith
authors.initials: FY
authors.lastname: Maaravi-Pinto
authors.forename: Athanasis
authors.initials: A
authors.lastname: Lourbopoulos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Grigoriadis
authors.forename: Abd-Al Roof
authors.initials: AA
authors.lastname: Higazi
authors.forename: Talma
authors.initials: T
authors.lastname: Brenner
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010960:Plasminogen Activators / Q000276:immunology / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000276:immunology / Q000378:metabolism*
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D010960:Plasminogen Activators