A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1

J Allergy Clin Immunol. 2014 Feb;133(2):448-60. doi: 10.1016/j.jaci.2013.10.048. Epub 2013 Dec 25.

Abstract

Background: Although the cytokine IL-31 has been implicated in inflammatory and lymphoma-associated itch, the cellular basis for its pruritic action is yet unclear.

Objective: We sought to determine whether immune cell-derived IL-31 directly stimulates sensory neurons and to identify the molecular basis of IL-31-induced itch.

Methods: We used immunohistochemistry and quantitative real-time PCR to determine IL-31 expression levels in mice and human subjects. Immunohistochemistry, immunofluorescence, quantitative real-time PCR, in vivo pharmacology, Western blotting, single-cell calcium imaging, and electrophysiology were used to examine the distribution, functionality, and cellular basis of the neuronal IL-31 receptor α in mice and human subjects.

Results: Among all immune and resident skin cells examined, IL-31 was predominantly produced by TH2 and, to a significantly lesser extent, mature dendritic cells. Cutaneous and intrathecal injections of IL-31 evoked intense itch, and its concentrations increased significantly in murine atopy-like dermatitis skin. Both human and mouse dorsal root ganglia neurons express IL-31RA, largely in neurons that coexpress transient receptor potential cation channel vanilloid subtype 1 (TRPV1). IL-31-induced itch was significantly reduced in TRPV1-deficient and transient receptor channel potential cation channel ankyrin subtype 1 (TRPA1)-deficient mice but not in c-kit or proteinase-activated receptor 2 mice. In cultured primary sensory neurons IL-31 triggered Ca(2+) release and extracellular signal-regulated kinase 1/2 phosphorylation, inhibition of which blocked IL-31 signaling in vitro and reduced IL-31-induced scratching in vivo.

Conclusion: IL-31RA is a functional receptor expressed by a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons and is a critical neuroimmune link between TH2 cells and sensory nerves for the generation of T cell-mediated itch. Thus targeting neuronal IL-31RA might be effective in the management of TH2-mediated itch, including atopic dermatitis and cutaneous T-cell lymphoma.

Keywords: AD; AITC; Allyl isothiocyanate; Atopic dermatitis; Cytokine; DRG; Dorsal root ganglia; ERK; Extracellular signal-regulated kinase; GRPR; Gastrin-releasing peptide receptor; HBSS; Hanks balanced salt solution; High-power field; IB4; Isolectin B4; KO; Knockout; MEK; Mas-related G protein–coupled receptor; Mitogen-activated protein kinase enzyme; Mrgpr; NPR-A; Natriuretic peptide receptor A; OSMRβ; OVA; Oncostatin M receptor β; Ovalbumin; PAR-2; Proteinase-activated receptor 2; Quantitative real-time PCR; SC; SEB; Spinal cord; Staphylococcal enterotoxin B; TG; TRPA1; TRPV1; Transient receptor channel potential cation channel ankyrin subtype 1; Transient receptor potential cation channel vanilloid subtype 1; Trigeminal ganglion; atopic dermatitis; hpf; qPCR; sensory nerve; skin; transient receptor potential channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels / immunology
  • Cells, Cultured
  • Female
  • Ganglia, Spinal / cytology
  • Humans
  • Interleukins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / immunology
  • Pruritus / immunology*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology*
  • Sensory Receptor Cells / immunology
  • Skin / immunology
  • TRPA1 Cation Channel
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / immunology
  • Th2 Cells / immunology*
  • Transient Receptor Potential Channels / immunology

Substances

  • Calcium Channels
  • IL31 protein, human
  • IL31RA protein, human
  • Il31ra protein, mouse
  • Interleukins
  • Nerve Tissue Proteins
  • Receptors, Interleukin
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • interleukin-31, mouse