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

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.
Ferda Cevikbas 1,  Xidao Wang 2,  Tasuku Akiyama 3,  Cordula Kempkes 4,  Terhi Savinko 5,  Attila Antal 6,  Gabriela Kukova 6,  Timo Buhl 4,  Akihiko Ikoma 4,  Joerg Buddenkotte 7,  Vassili Soumelis 8,  Micha Feld 6,  Harri Alenius 5,  Stacey R Dillon 9,  Earl Carstens 3,  Bernhard Homey 10,  Allan Basbaum 11,  Martin Steinhoff 12
Affiliations

Affiliations

  • 1 Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 2 Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif.
  • 3 Department of Neurobiology, Physiology and Behavior, University of California, Davis, Calif.
  • 4 Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.
  • 5 Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
  • 6 Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 7 Department of Dermatology, University Hospital Münster, Muenster, Germany.
  • 8 Department of Immunology, Institut Curie, Paris, France.
  • 9 ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.
  • 10 Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: [email protected].
  • 11 Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif. Electronic address: [email protected].
  • 12 Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: [email protected].
PMID: 24373353 DOI: 10.1016/j.jaci.2013.10.048
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.

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