Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia

Nat Commun. 2012;3:1119. doi: 10.1038/ncomms2127.

Abstract

Interleukin-17A, the prototypical member of the interleukin-17 cytokine family, coordinates local tissue inflammation by recruiting neutrophils to sites of infection. Dysregulation of interleukin-17 signalling has been linked to the pathogenesis of inflammatory diseases and autoimmunity. The interleukin-17 receptor family members (A-E) have a broad range of functional effects in immune signalling yet no known role has been described for the remaining orphan receptor, interleukin-17 receptor D, in regulating interleukin-17A-induced signalling pathways. Here we demonstrate that interleukin-17 receptor D can differentially regulate the various pathways employed by interleukin-17A. Neutrophil recruitment, in response to in vivo administration of interleukin-17A, is abolished in interleukin-17 receptor D-deficient mice, correlating with reduced interleukin-17A-induced activation of p38 mitogen-activated protein kinase and expression of the neutrophil chemokine MIP-2. In contrast, interleukin-17 receptor D deficiency results in enhanced interleukin-17A-induced activation of nuclear factor-kappa B and interleukin-6 and keratinocyte chemoattractant expression. Interleukin-17 receptor D disrupts the interaction of Act1 and TRAF6 causing differential regulation of nuclear factor-kappa B and p38 mitogen-activated protein kinase signalling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Connexin 43 / metabolism
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • HeLa Cells
  • Humans
  • Interleukin-17 / metabolism*
  • Interleukin-17 / pharmacology*
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration / drug effects
  • Peptide Fragments / metabolism
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TNF Receptor-Associated Factor 6 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ACT1 protein
  • Connexin 43
  • Interleukin-17
  • Interleukin-6
  • Peptide Fragments
  • Receptors, Interleukin-17
  • TNF Receptor-Associated Factor 6
  • p38 Mitogen-Activated Protein Kinases