952 Topical Nicotinic Receptor Activation Improves Wound Bacterial Infection Outcomes by Suppressing TLR2-mediated Inflammation in Diabetic Wounds

Chronic inflammation is frequently observed in diabetic wounds and can occur, in part, via excessive TLR2 activation or production. Consequently, this can delay physiologic wound healing responses and increase diabetic host susceptibility to bacterial infection. The cholinergic anti-inflammatory pathway can directly affect skin antibacterial and wound healing responses via nicotinic acetylcholine receptors (nAChRs). Specifically, epidermal α7 nAChR (CHRNA7) can modulate the host response to wounding and/or wound bacterial infection. We established that topical nAChR activation diminishes bacterial survival and systemic dissemination in a mouse model of diabetic wound infection, while reducing wound TLR2 production, relative to control mice. We further observed that the antimicrobial peptide activity of diabetic mouse wounds is increased compared to control mice, but this effect is lost following topical nAChR activation. Finally, skin from human diabetic wounds exhibited impaired α7 nAChR (CHRNA7) abundance and localization relative to human control (nondiabetic) skin. These findings indicate that topical administration of nAChR agonists may improve wound healing and infection outcomes in diabetic wounds by suppressing TLR2-mediated inflammation and antimicrobial peptide responses, and that the diabetic microenvironment may promote aberrant CHRNA7 production/activation that likely contributes to diabetic wound pathogenesis.