663 Activation of Trpv1+ nociceptive fibers stimulates an innate antiviral immune response following skin injury

Abstract

Multiple innate immune signaling pathways become activated upon skin injury in order to reestablish the antimicrobial barrier, prevent infection and excessive tissue injury. Damage to the skin barrier often elicits pain and leads to activation of cutaneous nociceptive fibers. We hypothesized that nociceptors in the skin are activated upon breach of the skin barrier and contribute to the innate antiviral response to skin injury. Here, we show that pharmacological or genetic ablation of TRPV1-mediated nociception impairs the innate antiviral response to skin injury. Using resiniferatoxin-treated mice or Trpv1-/- mice in murine skin excisional wound assays, we identified that preferential ablation of Trpv1 channels reduces the transcription of IFNb (p<0.01), IL27 (p<0.05), and multiple antiviral proteins including Oas2 and Oasl2 (p<0.05) in the skin. The neuromediator N-acetyl-galactosamine (GalNAc) is present in sensory nerves and binds with high specificity to the CD301 lectin, a marker for a subset of dendritic cells that releases IL-27 in the process of skin wound repair. We here show that human THP1-derived immature dendritic cells and Langerhans cells isolated from fresh human skin express IL27 when stimulated with GalNAc (p<0.01 and p<0.001, respectively). Given the knowledge from previous work that cathelicidin LL-37 is produced within the skin following injury and complexes with nucleic acids to enhance production of type I IFNs, we tested the possibility that LL-37 could also alter GalNAc signaling. We demonstrate that LL-37 with GalNAc significantly enhances IL27 (p<0.001), IFNa4 (p<0.01), and IFNb1 (p<0.01) production. Together, our data suggest that nociception promotes skin antiviral competence through activation of antiviral signaling pathways upon wounding. Better understanding of the role of pain and itch in stimulating antimicrobial peptide and protein expression and induction following injury is relevant for improving skin repair.