The Influence of Differentially Expressed Tissue-Type Plasminogen Activator in Experimental Autoimmune Encephalomyelitis: Implications for Multiple Sclerosis

Abstract

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.

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

“…Some reports indicate that tPA −/− mice present earlier and more severe disease that their WT counterparts, suggesting a protective role of tPA [12,31,32]. Other studies, including the present one, argue for a deleterious effect of tPA [11].…”

A critical role for plasminogen in inflammation

“…tPA is implicated in MS development and is up-regulated fourfold when EAE is induced. It seems to play a protective role in EAE, as tPA-deficient mice have an earlier onset and increased severity of demyelination (East et al, 2005; Dahl et al, 2016), likely because tPA is necessary to clear fibrin deposits on axons damaged during EAE progression. Axonal damage is a crucial contributor to MS progression, and fibrinogen has been shown to be a critical regulator of microglial activation and axonal damage in EAE (Davalos and Akassoglou, 2012).…”

Roles of the tissue-type plasminogen activator in immune response

“…The role of tPA in the T cell-mediated EAE model is still a matter of debate. Previous reports demonstrate an increase in tPA activity in EAE [56] , [57] . In addition, expression of tPA and its inhibitor PA1 transcripts are found in the sites of tissue damage and neuroinflammation suggesting an involvement of this serine protease in the EAE physiopathology [58] .…”

“…Initially, Lu et al described that tPA - / - developed a more severe form of EAE but with a delayed onset in the disease [57] . Although most studies corroborated this finding and showed a protective role of tPA [8] , [56] , [59] , others reported a detrimental function of tPA in the pathogenesis of EAE with either tPA deficiency which results in a less severe form of EAE or tPA administration that increases the severity of EAE [9] , [51] . These inconsistencies between several studies may be attributed to the differences in the experimental protocols including myelin antigen doses, sex and age of the animals or the number of immunizations/boosts.…”