Keratinocyte nicotinic acetylcholine receptor activation modulates early TLR2-mediated wound healing responses

- Keratinocyte nicotinic acetylcholine receptor (nAChR) activation dampens TLR2-mediated migration in a scratch wound assay.
- Antagonism of the alpha 7 nAChR restores TLR2-mediated migration and defects in intracellular MAPK and NFκB signaling.
- Topical nicotine reduces TLR2 and TLR2-dependent AMP production in S. aureus infected murine wounds.
- Topical nAChR antagonists may augment TLR2-mediated inflammation in non-healing wounds to improve wound healing outcomes.

The cholinergic anti-inflammatory pathway spans several macro- and micro-environments to control inflammation via α7 nicotinic acetylcholine receptors (nAChRs). Physiologic inflammation is necessary for normal wound repair and is triggered, in part, via Toll-like receptors (TLRs). Here, we demonstrate that keratinocyte nAChR activation dampens TLR2-mediated migration and pro-inflammatory cytokine and antimicrobial peptide (AMP) production, which is restored by a α7-selective nAChR antagonist. The mechanism of this response occurs by blocking the NF-κB and Erk1/2 pathway during early and late wound healing. In a mouse model of Staphylococcus aureus wound infection, topical nAChR activation reduces wound AMP and TLR2 production to augment bacterial survival in wild-type mice. These findings suggest that aberrant α7 nAChR activation may impair normal wound healing responses, and that pharmacologic administration of topical nAChR antagonists may improve wound healing outcomes in wounds necessitating a more robust inflammatory response.