Orphan receptor IL-17RD regulates Toll-like receptor signalling via SEFIR/TIR interactions

Nat Commun. 2015 Mar 26;6:6669. doi: 10.1038/ncomms7669.


Receptor families of the innate immune response engage in 'cross-talk' to tailor optimal immune responses against invading pathogens. However, these responses are subject to multiple levels of regulation to keep in check aberrant inflammatory signals. Here, we describe a role for the orphan receptor interleukin-17 receptor D (IL-17RD) in negatively regulating Toll-like receptor (TLR)-induced responses. Deficiency of IL-17RD expression in cells leads to enhanced pro-inflammatory signalling and gene expression in response to TLR stimulation, and Il17rd(-/-) mice are more susceptible to TLR-induced septic shock. We demonstrate that the intracellular Sef/IL-17R (SEFIR) domain of IL-17RD targets TIR adaptor proteins to inhibit TLR downstream signalling thus revealing a paradigm involving cross-regulation of members of the IL-17R and TLR families.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Line
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology*
  • Inflammation
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology*
  • Mice
  • Mice, Knockout
  • NF-kappa B / immunology*
  • Protein Structure, Tertiary
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Shock, Septic / genetics
  • Shock, Septic / immunology*
  • Signal Transduction
  • Toll-Like Receptors / immunology*
  • Toll-Like Receptors / metabolism


  • Adaptor Proteins, Signal Transducing
  • IL17RD protein, human
  • Il17rd protein, mouse
  • Interferon Regulatory Factors
  • NF-kappa B
  • Receptors, Interleukin
  • Toll-Like Receptors