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

Ferda Cevikbas, Xidao Wang, Tasuku Akiyama, Cordula Kempkes, Terhi Savinko, Attila Antal, Gabriela Kukova, Timo Buhl, Akihiko Ikoma, Joerg Buddenkotte, Vassili Soumelis, Micha Feld, Harri Alenius, Stacey R. Dillon, Earl Carstens, Bernhard Homey, Allan Basbaum, Martin Steinhoff

Research output: Contribution to journalArticlepeer-review

381 Scopus citations


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 Ca2+ 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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Feb 2014


  • atopic dermatitis
  • Cytokine
  • sensory nerve
  • skin
  • transient receptor potential channel

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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