title: Keratinocyte nicotinic acetylcholine receptor activation modulates early TLR2-mediated wound healing responses.
abstract: 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.
authors.affiliation: The Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Science Division, Maywood, IL, USA; Department of Surgery, Loyola University Chicago, Health Science Division, Maywood, IL, USA. Electronic address: kradek1@luc.edu.
authors.forename: Mari
authors.initials: M
authors.lastname: Kishibe
authors.affiliation: The Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Science Division, Maywood, IL, USA; Department of Surgery, Loyola University Chicago, Health Science Division, Maywood, IL, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Griffin
authors.affiliation: The Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Science Division, Maywood, IL, USA; Department of Surgery, Loyola University Chicago, Health Science Division, Maywood, IL, USA; Infectious Disease and Immunology Research Institute in the Department of Microbiology and Immunology, Loyola University Chicago, Health Science Division, Maywood, IL, USA; Stritch School of Medicine, Loyola University Chicago, Health Science Division, Maywood, IL, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Radek
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin; D013203:Staphylococcal Infections / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D011978:Receptors, Nicotinic; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D009538:Nicotine; D054804:Cathelicidins
keywords: Antimicrobial peptides; Infection; Keratinocytes; Nicotinic receptors; Toll-like receptor-2; Wound healing