Inflammation and coagulation are two main host-defence systems interacting with each other. Inflammation activates coagulation and coagulation modulates the inflammatory activity at different levels. Disturbances of their interplay significantly contribute to many human diseases.
Local inflammation and oxidative stress together with the scar formation at the lesion site are the most common pathways known to limit peripheral nerve regeneration. The failure in the regeneration of injured peripheral nerves can lead to motor and sensory deficits ending with paralysis and chronic pain of the affected areas. After peripheral nerve injury the activity of thrombin, the key mediator of coagulation, is known to rapidly rise partially coming from blood extravasation but also being locally generated.
Our previous data indicate that thrombin can favour or limit neural regeneration according to its concentration acting through its main receptor, the protease activated receptor 1 (PAR1). PAR1 is expressed in Schwann cells especially at the level of the nodes of Ranvier (Pompili et al., 2017; Pompili et al., 2020). Axonal regeneration in peripheral nerves is greatly supported by Schwann cells that after injury de-differentiate and guide axons to their original target tissue.
The present research project aims to analyse how different levels of thrombin affect the ability of Schwann cells to execute the autophagic removal of myelin and the production of inflammatory mediators in rodent primary cultures and ex vivo nerve explants. Our hypothesis is that thrombin acting through the JNK/c-Jun pathway affects the efficiency of the autophagic flux regulating myelin removal and the production of the pro-inflammatory mediator MIF (macrophage migration inhibitory factor) in Schwann cells. Our study will also consider the effect of different levels of thrombin on the proliferation of peripheral nerve fibroblasts since these cells are the main responsible of the scar formation after injury.
Peripheral nerve injuries can cause both sensory and motor deficits that may lead to devastating functional outcomes, including complete paralysis of the affected limb or intractable pain. This not only results in a significant decline in quality of life, but also leads to financial losses associated with the delayed recovery as these injuries most commonly affecting the young working population. In particular, there is an urgent need for new treatment options in the prevention and management of chronic pain. An estimated 20-30% of the world's adult population experience chronic pain (Gureje et al., 1998; Harstall, 2003). Present therapies are inadequate and poorly managed pain leads to physical and psychological disability, reduced quality of life, and significant cost burden to healthcare providers and society. In this connection, MIF has been recognized as a key regulator of pain and an enhancer of pain responses caused by stress (Alexander et al., 2012).
To date, there is no established adjuvant drug therapy in clinical practice, which would enhance the speed and quality of nerve regeneration. The comprehension of the neuronal/glial interaction is fundamental for understanding the pathophysiology of peripheral nerve injuries and for identifying novel druggable molecular targets.