Protease and protease-activated receptors as regulators of peripheral nerve regeneration

Coagulation and inflammation are tightly and reciprocally regulated. Inflammation initiates clotting, decreases the activity of natural anticoagulant mechanisms and impairs the fibrinolytic system. Thrombin is the main effector protease in hemostasis and it also plays a role in various non-hemostatic biological and pathophysiologic processes, predominantly mediated through activation of protease-activated receptors (PARs). PAR-1 is the main thrombin receptor in peripheral nerves and it is highly expressed at the level of non-compacted Schwann cell myelin microvilli of the nodes of Ranvier. After nerve crush thrombin is locally generated at the site of injury (Gera et al., 2018). The generation of thrombin is generally believed to have long-term beneficial effects for tissue repair. In this connection, our previous data indicate that PAR-1 activation on Schwann cells favors their ability to promote axonal regrowth after lesion (Pompili et al., 2017). On the other hand, it has also been reported that an excessive generation of thrombin can be detrimental for nerve functions. Our present data show that the morphology of the nodes appears to be deeply affected by high concentrations of thrombin (0.1-1 mM). In the thrombin-treated nerves we also observe a redistribution of S100b to the paranodes and the Schmidt- Lanterman incisures. Controlling thrombin concentration may preserve neuronal health during nerve injury and represent a novel target for pharmacologic therapies.