Interleukin-17 receptor D constitutes an alternative receptor for interleukin-17A important in psoriasis-like skin inflammation

Sci Immunol. 2019 Jun 7;4(36):eaau9657. doi: 10.1126/sciimmunol.aau9657.

Abstract

T helper 17 (TH17) cells and interleukin-17A (IL-17A) produced by them are critical in autoinflammatory diseases, such as psoriasis. IL-17A has been shown to signal through IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) complex to drive inflammatory responses. However, in a psoriasis model, we found that Il17rc deficiency did not completely ameliorate the disease, suggesting another receptor. In search for another IL-17A-interacting receptor, we found that IL-17RD directly bound IL-17A but not IL-17F or IL-17A/F heterodimer and formed a heterodimer with IL-17RA. IL-17A-, but not IL-17F- or IL-17A/F-, mediated gene expression was defective in Il17rd-deficient keratinocytes. Il17rd deficiency in nonhemopoietic cells attenuated imiquimod-induced psoriasis-like skin inflammation. Although IL-17RC and IL-17RD differentially activated IL-17A-dependent signaling and gene expression, their compound mutation led to complete deficits in keratinocytes. IL-23 was found induced by IL-17A in keratinocytes, dependent on both IL-17RC and IL-17RD, suggesting feed-forward regulation of IL-23/IL-17 axis in psoriasis. Together, IL-17RD constitutes a second functional receptor for IL-17A and, together with IL-17RC, mediates the proinflammatory gene expression downstream of IL-17A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Imiquimod
  • Interleukin-17 / immunology*
  • Keratinocytes / immunology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Psoriasis / chemically induced
  • Psoriasis / immunology*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Skin / immunology

Substances

  • IL17A protein, human
  • IL17RD protein, human
  • Interleukin-17
  • Receptors, Interleukin
  • Imiquimod