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The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention.

Gur-Wahnon D, Mizrachi T, Maaravi-Pinto FY, Lourbopoulos A, Grigoriadis N, Higazi AA, Brenner T - J Neuroinflammation (2013)

Bottom Line: Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Hadassah Medical Center, P,O, Box 12000, Jerusalem 91120, Israel. brenner@cc.huji.ac.il.

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.

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Experimental autoimmune encephalomyelitis (EAE) is aggravated in mice deficient for the urokinase plasminogen activator (uPA−/−), or the urokinase plasminogen activator receptor (uPAR−/−). (A) EAE clinical severity in uPA−/− mice and control wild-type (WT) mice. (B) EAE clinical severity in uPAR−/− mice and control WT mice. (A,B) Results are expressed as the mean clinical score ± standard error (SE) of three separate experiments (*P<0.05).
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Figure 1: Experimental autoimmune encephalomyelitis (EAE) is aggravated in mice deficient for the urokinase plasminogen activator (uPA−/−), or the urokinase plasminogen activator receptor (uPAR−/−). (A) EAE clinical severity in uPA−/− mice and control wild-type (WT) mice. (B) EAE clinical severity in uPAR−/− mice and control WT mice. (A,B) Results are expressed as the mean clinical score ± standard error (SE) of three separate experiments (*P<0.05).

Mentions: Several components of the plasminogen activation cascade have been found to be involved in CNS pathologies, including stroke, TBI, MS, and EAE. To evaluate the effect of uPA and uPAR on processes related to CNS inflammation, we examined their involvement in EAE, the experimental inflammatory and demyelinating autoimmune disease used to study human MS. EAE was induced in uPA−/− , uPAR−/−, and WT mice. All the KO mice tested presented more severe neurologic scores and delayed recovery compared with the WT mice (Figure 1). In the uPA−/− mice, the mean disease severity was 1.8 ± 0.2 compared with 1.1 ± 0.2 in the WT mice (a 64% increase) (Figure 1A). uPAR−/− mice had significantly more severe disease than the WT mice in the chronic phase of the disease (Figure 1B), with mean disease severity being 2.5 ± 0.4 for uPAR−/− versus 1.7 ± 0.2 for WT (a 47% increase over WT) (Figure 1B). Notably, whereas the WT mice showed remission of the disease about 30 days post-induction, both the uPA−/− and the uPAR−/− animals failed to recover.


The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention.

Gur-Wahnon D, Mizrachi T, Maaravi-Pinto FY, Lourbopoulos A, Grigoriadis N, Higazi AA, Brenner T - J Neuroinflammation (2013)

Experimental autoimmune encephalomyelitis (EAE) is aggravated in mice deficient for the urokinase plasminogen activator (uPA−/−), or the urokinase plasminogen activator receptor (uPAR−/−). (A) EAE clinical severity in uPA−/− mice and control wild-type (WT) mice. (B) EAE clinical severity in uPAR−/− mice and control WT mice. (A,B) Results are expressed as the mean clinical score ± standard error (SE) of three separate experiments (*P<0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852474&req=5

Figure 1: Experimental autoimmune encephalomyelitis (EAE) is aggravated in mice deficient for the urokinase plasminogen activator (uPA−/−), or the urokinase plasminogen activator receptor (uPAR−/−). (A) EAE clinical severity in uPA−/− mice and control wild-type (WT) mice. (B) EAE clinical severity in uPAR−/− mice and control WT mice. (A,B) Results are expressed as the mean clinical score ± standard error (SE) of three separate experiments (*P<0.05).
Mentions: Several components of the plasminogen activation cascade have been found to be involved in CNS pathologies, including stroke, TBI, MS, and EAE. To evaluate the effect of uPA and uPAR on processes related to CNS inflammation, we examined their involvement in EAE, the experimental inflammatory and demyelinating autoimmune disease used to study human MS. EAE was induced in uPA−/− , uPAR−/−, and WT mice. All the KO mice tested presented more severe neurologic scores and delayed recovery compared with the WT mice (Figure 1). In the uPA−/− mice, the mean disease severity was 1.8 ± 0.2 compared with 1.1 ± 0.2 in the WT mice (a 64% increase) (Figure 1A). uPAR−/− mice had significantly more severe disease than the WT mice in the chronic phase of the disease (Figure 1B), with mean disease severity being 2.5 ± 0.4 for uPAR−/− versus 1.7 ± 0.2 for WT (a 47% increase over WT) (Figure 1B). Notably, whereas the WT mice showed remission of the disease about 30 days post-induction, both the uPA−/− and the uPAR−/− animals failed to recover.

Bottom Line: Antigen presentation was also reduced in all the KO animals, raising an immunologic paradox.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Hadassah Medical Center, P,O, Box 12000, Jerusalem 91120, Israel. brenner@cc.huji.ac.il.

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.

Show MeSH
Related in: MedlinePlus