We previously reported that ADAM17 is a key protease regulating myelin formation. We now describe a role for ADAM17 during the Wallerian degeneration process. Unexpectedly, we observed that glial ADAM17, by regulating p75NTR processing, cell autonomously promotes remyelination, while neuronal ADAM17 is dispensable. Accordingly, p75NTR abnormally accumulates specifically when ADAM17 is maximally expressed leading to a down–regulation of tPA expression, excessive fibrin accumulation over time and delayed remyelination. Mutant mice also present impaired macrophage recruitment and defective nerve conduction velocity. Thus, ADAM17 expressed in Schwann cells, controls the whole Wallerian degeneration process and its absence hampers effective nerve repair. Collectively, we describe a previously uncharacterized role for glial ADAM17 during nerve regeneration. Based on the results of our study, we posit that, unlike development, glial ADAM17 promotes remyelination through the regulation of p75NTR –mediated fibrinol...