Nuclear Factor-κB Activation in Axons and Schwann Cells in Experimental Sciatic Nerve Injury and Its Role in Modulating Axon Regeneration: Studies With Etanercept

An increasing weight of evidence implicates early inflammatory events as inhibitors of functional recovery in both peripheral and central neuropathologies. In this study, we investigated the role of the inflammatory TNF-α/NF-κB axis on events subsequent to sciatic nerve crush injury in rats. Electrophoretic mobility shift assays (EMSA) revealed that within 6 hours post-crush NF-κB DNA binding activity increased significantly in a 1 cm section of sciatic nerve, centered on the crush site. Immunofluorescent staining for NF-κB subunits verified increased nuclear localization of p50, but not p65 or c-Rel, in Schwann cells, with no evidence of immune cell infiltration. In rats injected s.c. with etanercept, a TNF-α receptor chimera which binds free cytokine, the injury-induced rise in NF-κB DNA-binding activity was inhibited. Immunofluorescent staining confirmed that nuclear localization of NF-κB subunit p50 in Schwann cells was significantly lower in etanercept treated vs. control nerves following nerve injury. Axonal growth determined 3 days after nerve crush with immunofluorescent staining for GAP43 demonstrated that regeneration distance of leading axons from the site of nerve crush was significantly greater in etanercept treated animals than saline-treated controls. These data indicate that TNF-α mediates rapid activation of injury-induced NF-κB DNA binding in Schwann cells, and inhibits post-injury axonal sprouting.