The influence of differentially expressed tissue-type plasminogen activator in experimental autoimmune encephalomyelitis: Implications for multiple sclerosis
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Tissue type plasminogen activator (t-PA) has been implicated in the development of multiple sclerosis (MS) and in rodent models of experimental autoimmune encephalomyelitis (EAE). We show that levels of t-PA mRNA and activity are increased ~4 fold in the spinal cords of wild-type mice that are mice subjected to EAE. This was also accompanied with a significant increase in the levels of pro-matrix metalloproteinase 9 (pro-MMP-9) and an influx of fibrinogen. We next compared EAE severity in wild-type mice, t-PA-/- mice and T4+ transgenic mice that selectively over-express (~14-fold) mouse t-PA in neurons of the central nervous system. Our results confirm that t-PA deficient mice have an earlier onset and more severe form of EAE. T4+ mice, despite expressing higher levels of endogenous t-PA, manifested a similar rate of onset and neurological severity of EAE. Levels of proMMP-9, and extravasated fibrinogen in spinal cord extracts were increased in mice following EAE onset regardless of the absence or over-expression of t-PA wild-type. Interestingly, MMP-2 levels also increased in spinal cord extracts of T4+ mice following EAE, but not in the other genotypes. Hence, while the absence of t-PA confers a more deleterious form of EAE, neuronal over-expression of t-PA does not overtly protect against this condition with regards to symptom onset or severity of EAE.
Dahl, L. C. M., Nasa, Z., Chung, J., Niego, B., Tarlac, V., Ho, K. C. H., Galle, A. A., Petratos, S., Alderuccio, F. P., & Medcalf, R. L. (2016). The influence of differentially expressed tissue-type plasminogen activator in experimental autoimmune encephalomyelitis: Implications for multiple sclerosis. PLoS ONE, 11(7), [e0158653]. https://doi.org/10.1371/journal.pone.0158653