title: Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia.
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.
authors.affiliation: Department of Biology, Institute of Immunology, National University of Ireland Maynooth, Maynooth, Ireland.
authors.forename: Mark
authors.initials: M
authors.lastname: Mellett
authors.forename: Paola
authors.initials: P
authors.lastname: Atzei
authors.forename: Alan
authors.initials: A
authors.lastname: Horgan
authors.forename: Emily
authors.initials: E
authors.lastname: Hams
authors.forename: Thomas
authors.initials: T
authors.lastname: Floss
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Padraic G
authors.initials: PG
authors.lastname: Fallon
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C541130:ACT1 protein; D018031:Connexin 43; D020381:Interleukin-17; D015850:Interleukin-6; D010446:Peptide Fragments; D053722:Receptors, Interleukin-17; D048029:TNF Receptor-Associated Factor 6; D048051:p38 Mitogen-Activated Protein Kinases