Plasminogen Deficiency Delays the Onset and Protects from Demyelination and Paralysis in Autoimmune Neuroinflammatory Disease

Abstract

Multiple sclerosis (MS) is a neuroinflammatory, demyelinating disease of the CNS. Fibrinogen deposition at sites of blood-brain barrier breakdown is a prominent feature of neuroinflammatory disease and contributes to disease severity. Plasminogen, the primary fibrinolytic enzyme, also modifies inflammatory processes. We used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to evaluate the hypothesis that the loss of plasminogen would exacerbate neuroinflammatory disease. However, contrary to initial expectations, EAE-challenged plasminogen-deficient (Plg Ϫ ) mice developed significantly delayed disease onset and reduced disease severity compared with wild-type (Plg ϩ ) mice. Similarly, pharmacologic inhibition of plasmin activation with tranexamic acid also delayed disease onset. The T-cell response to immunization was similar between genotypes, suggesting that the contribution of plasminogen was downstream of the T-cell response. Spinal cords from EAE-challenged Plg Ϫ mice demonstrated significantly decreased demyelination and microglial/macrophage accumulation compared with Plg ϩ mice. Although fibrinogen-deficient mice or mice with combined deficiencies of plasminogen and fibrinogen had decreased EAE severity, they did not exhibit the delay in EAE disease onset, as seen in mice with plasminogen deficiency alone. Together, these data suggest that plasminogen and plasmin-mediated fibrinolysis is a key modifier of the onset of neuroinflammatory demyelination.

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“…These fibrinogen-deficient mice have been previously used to study the role of fibrinogen deficiency on defects in the AD mouse BBB 41 and in an experimental autoimmune encephalitis model 57 . We found that F7/F7; Fga +/- mice compared to F7/F7; Fga +/+ littermate controls develop substantial reductions in fibrinogen plasma levels (Fig.…”

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

“…This demonstrates an inhibitory effect of TXA on CNS tissue inflammation while enhancing immune activation in the cLN. This is consistent with previous reports implicating plasmin in inflammation, on the one hand, 32,33 and in immunosuppression, on the other. 10 A summary of the findings observed in plg −/− mice and in wild-type mice treated with TXA is shown in Table 2.…”

“…Plasmin has been described as a promoter of inflammation, yet recent findings suggest a more complex role in the modulation of immunity, including its ability to induce a tolerogenic phenotype to dendritic cells by reducing their capacity to induce an allogeneic immune response . Curiously, studies using plasminogen‐deficient mice have reported both reduced and exacerbated inflammatory responses, depending on the disease model: plasmin(ogen) deficiency can be deleterious in models of wound healing, yet protective in models of lipopolysaccharide‐induced and experimental autoimmune encephalomyelitis‐induced neuroinflammation indicating that plasminogen is needed to exert a complete inflammatory response.…”

Fibrinolysis: from blood to the brain

“…While the discussion above points to an immunosuppressive role for plasmin, other studies have reported that plasminogen is actually required to implement a full neuroinflammatory response . This clearly deviates from the current discussion and indicates that plasmin(ogen) may therefore function in different capacities with regards to inflammation and the immune response that may depend on the type of insult, magnitude and location.…”