Ferda Cevikbas1, Xidao Wang2, Tasuku Akiyama3, Cordula Kempkes4, Terhi Savinko5, Attila Antal6, Gabriela Kukova6, Timo Buhl4, Akihiko Ikoma4, Joerg Buddenkotte7, Vassili Soumelis8, Micha Feld6, Harri Alenius5, Stacey R Dillon9, Earl Carstens3, Bernhard Homey10, Allan Basbaum11, Martin Steinhoff12. 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: bernhard.homey@uni-duesseldorf.de. 11. 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. 12. 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.
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.
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 2mice. 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.
Authors: M Steinhoff; N Vergnolle; S H Young; M Tognetto; S Amadesi; H S Ennes; M Trevisani; M D Hollenberg; J L Wallace; G H Caughey; S E Mitchell; L M Williams; P Geppetti; E A Mayer; N W Bunnett Journal: Nat Med Date: 2000-02 Impact factor: 53.440
Authors: Martin Steinhoff; Ulrich Neisius; Akihiko Ikoma; Manigé Fartasch; Gisela Heyer; Per S Skov; Thomas A Luger; Martin Schmelz Journal: J Neurosci Date: 2003-07-16 Impact factor: 6.167
Authors: Stacey R Dillon; Cindy Sprecher; Angela Hammond; Janine Bilsborough; Maryland Rosenfeld-Franklin; Scott R Presnell; Harald S Haugen; Mark Maurer; Brandon Harder; Janet Johnston; Susan Bort; Sherri Mudri; Joseph L Kuijper; Tom Bukowski; Pamela Shea; Dennis L Dong; Maria Dasovich; Francis J Grant; Luann Lockwood; Steven D Levin; Cosette LeCiel; Kim Waggie; Heather Day; Stavros Topouzis; Janet Kramer; Rolf Kuestner; Zhi Chen; Don Foster; Julia Parrish-Novak; Jane A Gross Journal: Nat Immunol Date: 2004-06-06 Impact factor: 25.606
Authors: Shayne N Hassler; Moeno Kume; Juliet M Mwirigi; Ayesha Ahmad; Stephanie Shiers; Andi Wangzhou; Pradipta R Ray; Serge N Belugin; Dhananjay K Naik; Michael D Burton; Josef Vagner; Scott Boitano; Armen N Akopian; Gregory Dussor; Theodore J Price Journal: JCI Insight Date: 2020-06-04