IL-36γ Induced by the TLR3-SLUG-VDR Axis Promotes Wound Healing via REG3A

J Invest Dermatol. 2017 Dec;137(12):2620-2629. doi: 10.1016/j.jid.2017.07.820. Epub 2017 Jul 31.

Abstract

IL-36 family members are highly expressed in hyperproliferative keratinocytes and play an important role in the pathogenesis of skin diseases such as psoriasis. However, whether and how IL-36 cytokines are induced to promote wound healing remains unknown. Here we showed that skin injury increased the expression of IL-36γ to promote wound healing. Mechanistically, the expression of IL-36γ was induced by RNAs from damaged cells via the activation of toll-like receptor 3 (TLR3) and TIR-domain-containing adapter-inducing IFN-β (TRIF) followed by the induction of a zinc finger protein SLUG to abrogate the inhibitory effect of vitamin D receptor (VDR) on the promoter of IL-36γ gene. IL-36γ acted back on keratinocytes to induce REG3A, which regulated keratinocyte proliferation and differentiation, thus promoting wound re-epithelialization. These observations show that skin injury increases IL-36γ via the activation of TLR3-SLUG-VDR axis and that IL-36γ induces REG3A to promote wound healing. These findings also provide insights into pathways contributing to wound repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cytokines / metabolism
  • Humans
  • Inflammation
  • Interferon-beta / metabolism
  • Interleukin-1 / metabolism*
  • Keratinocytes / cytology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatitis-Associated Proteins / metabolism*
  • Psoriasis / pathology
  • RNA / metabolism
  • Receptors, Calcitriol / metabolism*
  • Signal Transduction
  • Skin / metabolism
  • Snail Family Transcription Factors / metabolism*
  • Toll-Like Receptor 3 / metabolism*
  • Wound Healing*

Substances

  • Cytokines
  • IL1F9 protein, mouse
  • IL36G protein, human
  • Interleukin-1
  • Pancreatitis-Associated Proteins
  • REG3A protein, human
  • Receptors, Calcitriol
  • Reg3a protein, mouse
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • TLR3 protein, human
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • VDR protein, human
  • RNA
  • Interferon-beta