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The pattern recognition receptor toll-like receptor 3 regulates skin barrier homeostasis /

  • Author(s): Borkowski, Andrew William
  • et al.
Abstract

Ultraviolet (UV) injury to the skin, and the subsequent release of non-coding double-stranded RNA (dsRNA) from necrotic keratinocytes, is an endogenous activator of Toll -like receptor 3 (TLR3). Because changes in keratinocyte growth and differentiation follow injury, we hypothesized that TLR3 might trigger some elements of the barrier repair program in keratinocytes and contribute to skin barrier repair. dsRNA was observed to induce TLR3- dependent increases in human keratinocyte mRNA abundance for ABCA12 (ATP-binding cassette, sub-family A, member 12), glucocerebrosidase, acid sphingomyelinase, and transglutaminase 1. Additionally tight junction gene expression and function is increased in keratinocytes treated with dsRNA. We also observe that treatment with dsRNA resulted in increases in sphingomyelin and increased epidermal lipid staining by oil-red O as well as TLR3- dependent increases in lamellar bodies and keratohyalin granules. Finally we demonstrate that Tlr3-/- mice display a delay in skin barrier repair following UVB damage. These data suggest that TLR3 participates in the program of skin barrier repair. Scavenger receptors can facilitate entry of dsRNA into airway epithelial cells. For this reason we hypothesized that scavenger receptors on keratinocytes could also facilitate entry of dsRNA into keratinocytes. We observe that scavenger receptor ligands block Poly (I: C) induced inflammatory responses in keratinocytes but surprisingly, can stimulate increases in ABCA12, GBA, and SMPD1 mRNA. Additionally, Msr1-/- mice display a skin barrier repair defect. These findings demonstrate an important role for scavenger receptors in skin barrier repair. UVB damage to the skin can lead to the activation of interleukin-1 receptor (IL-1R) which mediates carcinogenesis and can inhibit hair growth. Herein we show that Il1r-/- mice develop dermal hair cysts after chronic UVB exposure and that their skin contains significantly fewer macrophages. We also demonstrate that IL-1R signaling is required for barrier disruption after UVB exposure in mice, though does not significantly contribute to the upregulation of Poly (I:C)-induced skin barrier repair genes. These observations show that IL-1R signaling contributes to homeostasis in skin following UVB exposure. Taken together these studies broaden our understanding of cellular mechanisms that respond to UVB-damage in the skin

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