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Epithelial DLX3-dependent transcriptome maintains normal skin immune homeostasis

Friday, September 16, 2016 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NIAMS
IMMUNO-8

Authors

  • S Bhattacharya
  • JC Kim
  • G Nakato
  • Y Ogawa
  • M Udey
  • M Morasso

Abstract

DLX3, a homeobox transcription factor, is highly expressed in the epithelial compartment of skin and teeth. We previously reported that mice lacking DLX3 in epidermis had alopecia, skin barrier defects and enhanced IL-17-associated skin inflammation. Based on these observations, we hypothesized that the initial signals produced by Dlx3-null keratinocytes result in the infiltration of antigen-presenting cells and T cells into the dermis with subsequent IL-17A production. To identify the triggering signals from Dlx3-null keratinocytes and the reciprocal signaling crosstalk between epidermis and dermis that stimulate inflammation, we performed acute deletion of Dlx3 in adult epidermal keratinocytes using a tamoxifen-inducible K14cre-ERT system (K14creERT; Dlx3f/f). Using flow cytometry analysis, we identified dermal accumulations of macrophages and neutrophils within 3 days of tamoxifen-induced Dlx3 ablation, with enhanced infiltration after one week and two weeks after deletion. We also observed increased numbers of IL-17 secreting Vg4+gdT cells one week and two weeks after Dlx3 deletion. RNA-seq analysis of early (3 day) and late (1 and 2 week) time points in Dlx3-ablated skin showed that Sonic hedgehog and Wnt/β-catenin signaling pathways are altered initially, followed by cell cycle regulation impairment and subsequent production of pro-inflammatory cytokines IL-36, IL-6 and IL-12. Furthermore, two weeks after Dlx3 deletion there was a down-regulation of the anti-inflammatory cytokine IL-10 and up-regulation of pro-inflammatory IL-17 cytokine. Our preliminary results suggest a critical function of DLX3 in regulating mechanisms that are required for the maintenance of normal skin immune homeostasis.

Category: Immunology