Abstract
Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by relapsing/remitting or progressive motor and sensory defects. These neurologic deficits are secondary to autoimmune-mediated demyelination of neurons within the CNS. Autoreactive T cells that target myelin and local microglial cell activation are both central to disease pathogenesis. Blood brain barrier breakdown is an early feature of disease process and is associated with prominent fibrin(ogen) deposition in demyelinating plaques. Fibrin(ogen) was recently shown to contribute to the local destruction of myelin by supporting Mac-1-dependent neurodegenerative microglial activation events. Based on prior evidence that fibrin within CNS lesions is a driver of MS development, the established contribution of plasmin-mediated proteolysis to fibrin clearance, and the known expression of plasminogen activators within demyelinating plaques, we hypothesized: i) plasmin(ogen) is an important determinant of MS pathogenesis in vivo, and ii) the genetic elimination of plasminogen in mice challenged with a murine model of MS, experimental autoimmune encephalomyelitis (EAE), would significantly worsen CNS pathologies and exacerbate the loss of motor function relative to cohorts of EAE-challenged plasminogen-sufficient mice. Detailed studies of control and plasminogen-deficient (PlgNull) mice, revealed that plasmin(ogen) was a powerful modifier of EAE pathogenesis, but contrary to our initial working theory, we have found that PlgNull animals exhibit significantly decreased disease in comparison to wildtype animals. PlgNull mice have a prolonged time to onset of disease in comparison to wildtype animals. Further, severity of disease is diminished, with significantly fewer days of paralysis in the PlgNull animals. PlgNull animals were also protected from the weight loss associated with the neuroinflammatory disease. Histologic analysis of spinal cords from challenged animals harvested at the peak of the disease course revealed diminished inflammation as well as decreased demyelination in mice lacking plasminogen. Somewhat counterintuitively, we further noted that fibrin(ogen) deposition within the spinal cords of challenged animals was decreased in the PlgNull mice compared to EAE-challenged wildtype controls. Diminished fibrin(ogen) deposition corresponded with fewer microglial cells accumulating within the cords of PlgNull mice. We have further shown that T cell response to the immunization initiating EAE is similar in both PlgNull and control animals, demonstrating that a genotype-dependent difference in the underlying autoimmune response is not the basis for the dampened neuroinflammatory disease in PlgNull mice. In summary, these studies directly show for the first time that plasminogen contributes to the development of paralysis and disease severity in an established murine model of MS. The biological impact of plasminogen on CNS pathobiology appears to be downstream of the T cell response in the immunized animals, and potentially related to a fibrin-independent contribution of plasmin-mediated proteolysis in local blood-brain barrier breakdown or microglial activation. We are currently working to elucidate the precise mechanism(s) whereby plasmin(ogen) alters CNS disease severity, but favor the concept of potentially antagonistic fibrin(ogen)-dependent and -independent mechanisms. The present studies underscore the notion that targeting hemostatic factors, in general, and plasminogen, in particular, may be a novel and effective therapeutic strategy in impeding the development or progression of multiple sclerosis.
Disclosures:
Mullins: Baxter: Consultancy.
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