Prostaglandin E2 (PGE2)-EP2 signaling negatively regulates murine atopic dermatitis-like skin inflammation by suppressing thymic stromal lymphopoietin expression

J Allergy Clin Immunol. 2019 Nov;144(5):1265-1273.e9. doi: 10.1016/j.jaci.2019.06.036. Epub 2019 Jul 11.

Abstract

Background: Atopic dermatitis (AD) is a common and chronic inflammatory skin disease of type 2 immunity. Keratinocyte-derived cytokines, including thymic stromal lymphopoietin (TSLP) and IL-33, are considered to induce the development of AD. Production of prostanoids, a family of lipid mediators, is increased in AD lesions. However, their physiologic functions remain to be clarified.

Objectives: We sought to elucidate the functions of prostanoids in the development of AD.

Methods: The roles of prostanoids were investigated in a mouse model of AD induced by repeated application of hapten and PAM212, a keratinocyte cell line.

Results: Application of indomethacin, which blocks prostanoid synthesis, leads to enhanced TSLP and IL-33 production in the skin, increased serum IgE levels, and exacerbation of skin inflammation in this AD model. The skin inflammation was attenuated in TSLP receptor-deficient mice but not in IL-33-deficient mice, and the indomethacin-enhanced type 2 immune responses were abolished in TSLP receptor-deficient mice. Indomethacin increased protease-activated receptor 2-mediated TSLP production in keratinocytes in vitro, and prostaglandin E2 reversed the increase in TSLP levels through its receptor, the prostaglandin E2 receptor (EP2), by downregulating surface expression of protease-activated receptor 2. Administration of an EP2 agonist canceled indomethacin-enhanced TSLP production and type 2 immune responses in the skin, whereas an EP2 antagonist caused an enhancement of TSLP production and type 2 immune responses in the skin.

Conclusion: Prostaglandin E2-EP2 signaling negatively regulates murine AD-like skin inflammation by suppressing TSLP expression.

Keywords: IL-33; Prostaglandin E(2); prostaglandin E(2) receptor; protease-activated receptor 2; thymic stromal lymphopoietin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / metabolism*
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism*
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism
  • Signal Transduction
  • Skin / metabolism*
  • Skin / pathology

Substances

  • Immunoglobulins
  • Interleukin-33
  • Receptors, Cytokine
  • Receptors, Prostaglandin E, EP2 Subtype
  • Tslpr protein, mouse
  • Dinoprostone