UC San Diego

Tumor necrosis factor (TNFɑ) is a proinflammatory cytokine that is upregulated in Schwann cells (SC) during Wallerian degeneration (WD) and has also been implicated in neuropathic pain. TNFɑ may be a connecting factor that leads the inflammatory response in WD to turn neuropathic. Understanding how TNFɑ is regulated during WD may provide more insight as to how elevated TNFɑ contributes to the occurrence of neuropathic pain after a peripheral nerve injury. Previous studies done in our lab have demonstrated that Schwann cell derived extracellular vesicles (SC EVs) block TNFɑ signaling on primary cultured SCs, but the biological mechanism of how SC EVs may play a role in TNFɑ regulation remain unclear. We observed that EVs isolated from SCs are enriched with TNFR1, the main binding receptor for soluble TNFɑ. To elucidate how TNFɑ may be regulated, we performed binding studies validating that TNFɑ can bind to the TNFR1 on SC EVs. We also show that SC EVs attenuate the effects of TNFɑ in vitro by analyzing the morphology of SCs treated with TNFɑ and SC EVs. Our studies suggest that TNFɑ binds to the TNFR1 on SC EVs, thus it can be argued that the presence of EVs decrease TNFɑ/TNFR1 signaling produced by SCs after a nerve injury. In conclusion, this mechanism is significant to understanding how elevatedexpression of TNFɑ is regulated during WD and offers some perspective on how elevated TNFɑ expression perpetuates neuropathic pain.