Effects mediated by α7 nicotinic receptors activation in Schwann cells: implication in peripheral nerve regeneration

Schwann cells (SCs) play a strategic role after peripheral nerve injury, driving axons regeneration and regulating local inflammation Recently we demonstrated the presence of a7 nicotinic acetylcholine receptors (nAChRs) in rat SCs. a7 nAChR is expressed in SCs after peripheral nerve axotomy and its expression is significantly enhanced after 24 h when sciatic nerve segments are cultured alone or ni presence of the proinflammatory neuropeptide Bradykinin (BK). To clarify the role that a7 nAChRs play after peripheral axon damage, we investigated the signal transduction pathways triggered by receptor activation and the effects produced by their activation. Both ionotropic and metabotropic signaling pathway were analyzed by calcium imaging and Western blot analysis, respectively, following a7 nAChF activation by partial agonist ICH3. In addition, the expression of c-Jun was evaluated by immunocytochemistry and Western blot analysis Finally, the cell migration was studied by a wound healing assay. Activation of a7 nAChRs by the selective partial agonist ICH3, did not induce calcium mobilization in SCs but positively modulated the metabotropic pathway involving PIK/AKT/mTORC1 axis. Activation of the MTOR complex was confirmed by the up-regulated expression of its specific p-p70 S6K hr389 target. Moreover, the up-regulation of p A M P K Ihr172 a negative regu lator or myelination, was also observed concomita ntly to an increased nuclear accumulation of the transcription factor c-Jun. Cell migration and morphology analyses demonstrate that a7 nAChR activation also promotes SCs migration Moreover a7 nAChRs caused an upregulation of uPA, MMP2 and MMP9 activity and decrease the IL-6 production and release. Thes results demonstrate that ACh, probably released from regenerating axons or by SC themselves, may actively promote, through a nAChRs activation the Repair Schwann Cell phenotype and contribute to favour an anti-inflammatory microenvironment. These conditions are relevant to support tne perpneral nerve regeneration.