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

Int Immunopharmacol. 2015 Nov;29(1):63-70. doi: 10.1016/j.intimp.2015.05.047. Epub 2015 Jun 10.

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.

Keywords: Antimicrobial peptides; Infection; Keratinocytes; Nicotinic receptors; Toll-like receptor-2; Wound healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides
  • Cytokines / metabolism
  • Gene Expression Regulation / physiology*
  • Humans
  • Keratinocytes / physiology*
  • Methicillin-Resistant Staphylococcus aureus
  • Mice
  • Mice, Inbred C57BL
  • Nicotine
  • Receptors, Nicotinic / metabolism*
  • Signal Transduction
  • Skin
  • Staphylococcal Infections / microbiology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Wound Healing / physiology*

Substances

  • Antimicrobial Cationic Peptides
  • Cytokines
  • Receptors, Nicotinic
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • CAP18 lipopolysaccharide-binding protein
  • Nicotine