title: A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Ferda
authors.initials: F
authors.lastname: Cevikbas
authors.affiliation: Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif.
authors.forename: Xidao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California, Davis, Calif.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.
authors.forename: Cordula
authors.initials: C
authors.lastname: Kempkes
authors.affiliation: Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Antal
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kukova
authors.affiliation: Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.
authors.forename: Timo
authors.initials: T
authors.lastname: Buhl
authors.affiliation: Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ikoma
authors.affiliation: Department of Dermatology, University Hospital Münster, Muenster, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Buddenkotte
authors.affiliation: Department of Immunology, Institut Curie, Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Soumelis
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Micha
authors.initials: M
authors.lastname: Feld
authors.affiliation: Unit of Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Alenius
authors.affiliation: ZymoGenetics (a Bristol-Myers Squibb Company), Seattle, Wash.
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.affiliation: Department of Neurobiology, Physiology and Behavior, University of California, Davis, Calif.
authors.forename: Earl
authors.initials: E
authors.lastname: Carstens
authors.affiliation: Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: bernhard.homey@uni-duesseldorf.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.affiliation: Department of Anatomy and the W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, Calif. Electronic address: Allan.Basbaum@ucsf.edu.
authors.forename: Allan
authors.initials: A
authors.lastname: Basbaum
authors.affiliation: Departments of Dermatology and Surgery, University of California, San Francisco, San Francisco, Calif; Department of Dermatology, University Hospital Düsseldorf, Düsseldorf, Germany. Electronic address: SteinhoffM@derm.ucsf.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D007378:Interleukins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000276:immunology; D011537:Pruritus / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D011984:Sensory Receptor Cells / Q000276:immunology; D012867:Skin / Q000276:immunology; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D050051:Transient Receptor Potential Channels / Q000276:immunology
chemical_list: D015220:Calcium Channels; C502187:IL31 protein, human; C502188:IL31RA protein, human; C488159:Il31ra protein, mouse; D007378:Interleukins; D009419:Nerve Tissue Proteins; D018123:Receptors, Interleukin; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C502588:interleukin-31, mouse
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