Schwann cells play an important role in peripheral nerve regeneration. Upon nerve injury, Schwann cells are activated and produce various proinflammatory cytokines and chemokines, resulting in the recruitment of macrophages and the phagocytosis of myelin debris. However, it is unclear how nerve injury induces Schwann cell activation. Recently, it was reported that necrotic cells induce immune cell activation via toll-like receptors (TLRs). This suggests that the TLRs expressed on Schwann cells may recognize nerve injury by binding to the endogenous ligands secreted by the damaged nerve, thereby inducing Schwann cell activation. To explore such a possibility, we stimulated rat Schwann cells with necrotic neuronal cells (NNC). The stimulation of Schwann cells with NNC induced the expression of various inflammatory mediators, including TNF-alpha and iNOS. Studies on the NNC-mediated intracellular signaling pathways revealed that p38 and JNK are involved in the NNC-mediated Schwann cell activation. In addition, NNC-induced proinflammatory gene expression was reduced in mouse Schwann cells derived from TLR2 or TLR3 knockout mice. In summary, these results suggest that necrotic neuronal cells induce inflammatory Schwann cell activation via TLR2 and TLR3, which might be involved in Wallerian degeneration upon peripheral nerve injury. (c) 2006 Elsevier Inc. All rights reserved.