TNFα-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve

Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is induced hours after injury to peripheral nerve. This study shows that MMP-9 gene deletion and neutralization with MMP-9 antibody reduce macrophage content in injured wild-type nerves. In mice with delayed Wallerian degeneration (WldS), MMP-9 and tumor necrosis factor alpha (TNFα) decline in association with the reduced macrophage recruitment to injured nerve that characterizes this strain of mice. We further determined that TNFα acts as an MMP-9 inducer by establishing increased MMP-9 levels after TNFα injection in rat sciatic nerve in vivo and primary Schwann cells in vitro. We found reduced MMP-9 expression in crushed TNFα knockout nerves that was rescued with exogenous TNFα. Finally, local application of MMP-9 on TNFα−/− nerves increased macrophage recruitment to the lesion. These data suggest that TNFα lies upstream of MMP-9 in the pathway of macrophage recruitment to injured peripheral nerve.