Tissue plasminogen activator-mediated fibrinolysis protects against axonaldegeneration and demyelination after sciatic nerve injury

Tissue plasminogen activator (tPA) is a serine protease that converts plasm inogen to plasmin and can trigger the degradation of extracellular matrix: proteins, In the nervous system, under noninflammatory conditions, tPA cont ributes to excitotoxic neuronal death, probably through degradation of lami nin. To evaluate the contribution of extracellular proteolysis in inflammat ory neuronal degeneration, we performed sciatic nerve injury in mice. Prote olytic activity was increased in the nerve after injury, and this activity was primarily because of Schwann cell-produced tPA, To identify whether tPA release after nerve damage played a beneficial or deleterious role, we cru shed the sciatic nerve of mice deficient for tPA, Axonal demyelination was exacerbated in the absence of tPA or plasminogen, indicating that tPA has a protective role in nerve injury, and that this protective effect is due to its proteolytic action on plasminogen. Axonal damage was correlated with i ncreased fibrin(ogen) deposition, suggesting that this protein might play a role in neuronal injury. Consistent with this idea, the increased axonal d egeneration phenotype in tPA- or plasminogen-deficient mice was ameliorated by genetic or pharmacological depletion of fibrinogen, identifying fibrin as the plasmin substrate in the nervous system under inflammatory axonal da mage. This study shows that fibrin deposition exacerbates axonal injury, an d that induction of an extracellular proteolytic cascade is a beneficial re sponse of the tissue to remove fibrin, tPA/plasmin-mediated fibrinolysis ma y be a widespread protective mechanism in neuroinflammatory pathologies.